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Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations
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Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Computational and Theoretical Chemistry".

Deadline for manuscript submissions: closed (7 September 2018) | Viewed by 88361

Special Issue Editors

Prof. Dr. Hai Lin

E-Mail Website
Guest Editor
University of Colorado Denver, Denver, CO 80217, USA
Interests: multi-scale modeling; combined QM/MM; ion solvation and transport; membrane proteins; enzymatic reactions
Prof. Dr. Donald G. Truhlar

grade E-Mail Website
Guest Editor
Department of Chemistry, Chemical Theory Center, Inorganometallic Catalyst Design Center, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455-0431, USA
Interests: chemical dynamics; catalysis; photochemistry; molecular modeling; computational thermodyanmics; electronic structure theory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Combined quantum-mechanics/molecular-mechanics (QM/MM) is an important component of many methods for in multi-scale modelling and simulations. The algorithms involve partitioning an entire system into a small subsystem of primary interest, which is modeled by an accurate QM level of theory, and the surroundings that interact with it, which are treated by MM force fields for computational efficiency. The surroundings may include the less active part of a large molecule, the solvent, all or part of a protein, or more than one of these—or other possibilities. The integration of QM and MM methods makes it affordable to realistically describe reactions in complex environments. QM/MM has found applications in many research fields such as enzymatic reactions and other catalytic reactions, ion solvation and transport, photochemistry, nanostructured materials, etc.

This Special Issue of Molecules, “Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations,” presents both recent developments and applications in this exciting field.

Prof. Hai Lin
Prof. Dr. Donald G. Truhlar
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • embedding theory and calculations
  • enzyme catalysis
  • heterogeneous catalysis
  • molecular mechanics
  • multi-scale modeling
  • photochemistry
  • polarization
  • quantum mechanics
  • reaction dynamics
  • solvation and transport

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Published Papers (22 papers)

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Research

12 pages, 10822 KiB  
Article
Simulating DNA Chip Design Using All-Electronic Graphene-Based Substrates
by Ernane de Freitas Martins, Gustavo Troiano Feliciano, Ralph Hendrik Scheicher and Alexandre Reily Rocha
Molecules 2019, 24(5), 951; https://doi.org/10.3390/molecules24050951 - 08 Mar 2019
Cited by 6 | Viewed by 3099
Abstract
In this paper, we present a theoretical investigation of an all-electronic biochip based on graphene to detect DNA including a full dynamical treatment for the environment. Our proposed device design is based on the changes in the electronic transport properties of graphene interacting [...] Read more.
In this paper, we present a theoretical investigation of an all-electronic biochip based on graphene to detect DNA including a full dynamical treatment for the environment. Our proposed device design is based on the changes in the electronic transport properties of graphene interacting with DNA strands under the effect of the solvent. To investigate these systems, we applied a hybrid methodology, combining quantum and classical mechanics (QM/MM) coupled to non-equilibrium Green’s functions, allowing for the calculations of electronic transport. Our results show that the proposed device has high sensitivity towards the presence of DNA, and, combined with the presence of a specific DNA probe in the form of a single-strand, it presents good selectivity towards specific nucleotide sequences. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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28 pages, 1992 KiB  
Article
The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations
by Fiona L. Kearns, Luke Warrensford, Stefan Boresch and H. Lee Woodcock
Molecules 2019, 24(4), 681; https://doi.org/10.3390/molecules24040681 - 14 Feb 2019
Cited by 10 | Viewed by 5100
Abstract
Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , [...] Read more.
Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , remains to be the most challenging step within an indirect FES protocol. To improve calculations of Δ A l o w → h i g h , we must: (1) compare the performance of all FES methods currently available; and (2) compile and maintain datasets of Δ A l o w → h i g h calculated for a wide-variety of molecules so that future practitioners may replicate or improve upon the current state-of-the-art. Towards these two aims, we introduce a new dataset, “HiPen”, which tabulates Δ A g a s M M → 3 o b (the free energy associated with switching from an M M to an S C C − D F T B molecular description using the 3ob parameter set in gas phase), calculated for 22 drug-like small molecules. We compare the calculation of this value using free energy perturbation, Bennett’s acceptance ratio, Jarzynski’s equation, and Crooks’ equation. We also predict the reliability of each calculated Δ A g a s M M → 3 o b by evaluating several convergence criteria including sample size hysteresis, overlap statistics, and bias metric ( Π ). Within the total dataset, three distinct categories of molecules emerge: the “good” molecules, for which we can obtain converged Δ A g a s M M → 3 o b using Jarzynski’s equation; “bad” molecules which require Crooks’ equation to obtain a converged Δ A g a s M M → 3 o b ; and “ugly” molecules for which we cannot obtain reliably converged Δ A g a s M M → 3 o b with either Jarzynski’s or Crooks’ equations. We discuss, in depth, results from several example molecules in each of these categories and describe how dihedral discrepancies between levels of theory cause convergence failures even for these gas phase free energy simulations. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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26 pages, 17288 KiB  
Article
Quantum Mechanical/Molecular Mechanical Analysis of the Catalytic Mechanism of Phosphoserine Phosphatase
by Dieter Krachtus, Jeremy C. Smith and Petra Imhof
Molecules 2018, 23(12), 3342; https://doi.org/10.3390/molecules23123342 - 17 Dec 2018
Cited by 7 | Viewed by 3369
Abstract
Phosphoserine phosphatase (PSP), a member of the haloacid dehalogenase (HAD) superfamily that comprises the vast majority of phosphotransferases, is likely a steady-state regulator of the level of d-serine in the brain. The proposed catalytic cycle of PSP consists of a two-step mechanism: [...] Read more.
Phosphoserine phosphatase (PSP), a member of the haloacid dehalogenase (HAD) superfamily that comprises the vast majority of phosphotransferases, is likely a steady-state regulator of the level of d-serine in the brain. The proposed catalytic cycle of PSP consists of a two-step mechanism: formation of a phospho-enzyme intermediate by phosphate transfer to Asp11 and its subsequent hydrolysis. Our combined quantum mechanical/molecular mechanical (QM/MM) calculations of the reaction pathways favour a dissociative mechanism of nucleophilic substitution via a trigonal-planar metaphosphate-like configuration for both steps, associated with proton transfer to the leaving group or from the nucleophile. This proton transfer is facilitated by active site residue Asp13 that acts as both a general base and a general acid. Free energy calculation on the reaction pathways further support the structural role of the enzymatic environment and the active site architecture. The choice of a proper reaction coordinate along which to bias the free energy calculations can be guided by a projection of the canonical reaction coordinate obtained from a chain-of-state optimisation onto important internal coordinates. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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17 pages, 551 KiB  
Article
A QM/MM Derived Polarizable Water Model for Molecular Simulation
by Koen M. Visscher, William C. Swope and Daan P. Geerke
Molecules 2018, 23(12), 3131; https://doi.org/10.3390/molecules23123131 - 29 Nov 2018
Cited by 8 | Viewed by 3283
Abstract
In this work, we propose an improved QM/MM-based strategy to determine condensed-phase polarizabilities and we use this approach to optimize a new and simple polarizable four-site water model for classical molecular simulation. For the determination of the model value for the polarizability from [...] Read more.
In this work, we propose an improved QM/MM-based strategy to determine condensed-phase polarizabilities and we use this approach to optimize a new and simple polarizable four-site water model for classical molecular simulation. For the determination of the model value for the polarizability from QM/MM, we show that our proposed consensus-fitting strategy significantly reduces the uncertainty in calculated polarizabilities in cases where the size of the local external electric field is small. By fitting electrostatic, polarization and dispersion properties of our water model based on quantum and/or combined QM/MM calculations, only a single model parameter (describing exchange repulsion) is left for empirical calibration. The resulting model performs well in describing relevant pure-liquid thermodynamic and transport properties, which illustrates the merit of our approach to minimize the number of free variables in our model. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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16 pages, 2992 KiB  
Article
A QM/MM Study of Nitrite Binding Modes in a Three-Domain Heme-Cu Nitrite Reductase
by Kakali Sen, Michael A. Hough, Richard W. Strange, Chin W. Yong and Thomas W. Keal
Molecules 2018, 23(11), 2997; https://doi.org/10.3390/molecules23112997 - 16 Nov 2018
Cited by 5 | Viewed by 3098
Abstract
Copper-containing nitrite reductases (CuNiRs) play a key role in the global nitrogen cycle by reducing nitrite (NO2−) to nitric oxide, a reaction that involves one electron and two protons. In typical two-domain CuNiRs, the electron is acquired from an external [...] Read more.
Copper-containing nitrite reductases (CuNiRs) play a key role in the global nitrogen cycle by reducing nitrite (NO2−) to nitric oxide, a reaction that involves one electron and two protons. In typical two-domain CuNiRs, the electron is acquired from an external electron-donating partner. The recently characterised Rastonia picketti (RpNiR) system is a three-domain CuNiR, where the cupredoxin domain is tethered to a heme c domain that can function as the electron donor. The nitrite reduction starts with the binding of NO2− to the T2Cu centre, but very little is known about how NO2− binds to native RpNiR. A recent crystallographic study of an RpNiR mutant suggests that NO2− may bind via nitrogen rather than through the bidentate oxygen mode typically observed in two-domain CuNiRs. In this work we have used combined quantum mechanical/molecular mechanical (QM/MM) methods to model the binding mode of NO2− with native RpNiR in order to determine whether the N-bound or O-bound orientation is preferred. Our results indicate that binding via nitrogen or oxygen is possible for the oxidised Cu(II) state of the T2Cu centre, but in the reduced Cu(I) state the N-binding mode is energetically preferred. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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24 pages, 5861 KiB  
Article
Interfacing CRYSTAL/AMBER to Optimize QM/MM Lennard–Jones Parameters for Water and to Study Solvation of TiO2 Nanoparticles
by Asmus Ougaard Dohn, Daniele Selli, Gianluca Fazio, Lorenzo Ferraro, Jens Jørgen Mortensen, Bartolomeo Civalleri and Cristiana Di Valentin
Molecules 2018, 23(11), 2958; https://doi.org/10.3390/molecules23112958 - 13 Nov 2018
Cited by 9 | Viewed by 4352
Abstract
Metal oxide nanoparticles (NPs) are regarded as good candidates for many technological applications, where their functional environment is often an aqueous solution. The correct description of metal oxide electronic structure is still a challenge for local and semilocal density functionals, whereas hybrid functional [...] Read more.
Metal oxide nanoparticles (NPs) are regarded as good candidates for many technological applications, where their functional environment is often an aqueous solution. The correct description of metal oxide electronic structure is still a challenge for local and semilocal density functionals, whereas hybrid functional methods provide an improved description, and local atomic function-based codes such as CRYSTAL17 outperform plane wave codes when it comes to hybrid functional calculations. However, the computational cost of hybrids are still prohibitive for systems of real sizes, in a real environment. Therefore, we here present and critically assess the accuracy of our electrostatic embedding quantum mechanical/molecular mechanical (QM/MM) coupling between CRYSTAL17 and AMBER16, and demonstrate some of its capabilities via the case study of TiO2 NPs in water. First, we produced new Lennard–Jones (LJ) parameters that improve the accuracy of water–water interactions in the B3LYP/TIP3P coupling. We found that optimizing LJ parameters based on water tri- to deca-mer clusters provides a less overstructured QM/MM liquid water description than when fitting LJ parameters only based on the water dimer. Then, we applied our QM/MM coupling methodology to describe the interaction of a 1 nm wide multilayer of water surrounding a spherical TiO2 nanoparticle (NP). Optimizing the QM/MM water–water parameters was found to have little to no effect on the local NP properties, which provide insights into the range of influence that can be attributed to the LJ term in the QM/MM coupling. The effect of adding additional water in an MM fashion on the geometry optimized nanoparticle structure is small, but more evident effects are seen in its electronic properties. We also show that there is good transferability of existing QM/MM LJ parameters for organic molecules–water interactions to our QM/MM implementation, even though these parameters were obtained with a different QM code and QM/MM implementation, but with the same functional. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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17 pages, 1541 KiB  
Article
Assessing Configurational Sampling in the Quantum Mechanics/Molecular Mechanics Calculation of Temoporfin Absorption Spectrum and Triplet Density of States
by Martina De Vetta, Omar Baig, Dorika Steen, Juan J. Nogueira and Leticia González
Molecules 2018, 23(11), 2932; https://doi.org/10.3390/molecules23112932 - 09 Nov 2018
Cited by 9 | Viewed by 4193
Abstract
The absorption properties of Temoporfin, a second-generation photosensitizer employed in photodynamic therapy, are calculated with an electrostatic-embedding quantum mechanics/molecular mechanics (QM/MM) scheme in methanol. The suitability of several ensembles of geometries generated by different sampling techniques, namely classical-molecular-dynamics (MD) and QM/MM-MD thermal sampling, [...] Read more.
The absorption properties of Temoporfin, a second-generation photosensitizer employed in photodynamic therapy, are calculated with an electrostatic-embedding quantum mechanics/molecular mechanics (QM/MM) scheme in methanol. The suitability of several ensembles of geometries generated by different sampling techniques, namely classical-molecular-dynamics (MD) and QM/MM-MD thermal sampling, Wigner quantum sampling and a hybrid protocol, which combines the thermal and quantum approaches, is assessed. It is found that a QM description of the chromophore during the sampling is needed in order to achieve a good agreement with respect to the experimental spectrum. Such a good agreement is obtained with both QM/MM-MD and Wigner samplings, demonstrating that a proper description of the anharmonic motions of the chromophore is not relevant in the computation of the absorption properties. In addition, it is also found that solvent organization is a rather fast process and a long sampling is not required. Finally, it is also demonstrated that the same exchange-correlation functional should be employed in the sampling and in the computation of the excited states properties to avoid unphysical triplet states with relative energies close or below 0 eV. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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15 pages, 4560 KiB  
Article
Hydration Thermodynamics of Non-Polar Aromatic Hydrocarbons: Comparison of Implicit and Explicit Solvation Models
by Hankyul Lee, Hyung-Kyu Lim and Hyungjun Kim
Molecules 2018, 23(11), 2927; https://doi.org/10.3390/molecules23112927 - 09 Nov 2018
Cited by 14 | Viewed by 5137
Abstract
The precise description of solute-water interactions is essential to understand the chemo-physical nature in hydration processes. Such a hydration thermodynamics for various solutes has been explored by means of explicit or implicit solvation methods. Using the Poisson-Boltzmann solvation model, the implicit models are [...] Read more.
The precise description of solute-water interactions is essential to understand the chemo-physical nature in hydration processes. Such a hydration thermodynamics for various solutes has been explored by means of explicit or implicit solvation methods. Using the Poisson-Boltzmann solvation model, the implicit models are well designed to reasonably predict the hydration free energies of polar solutes. The implicit model, however, is known to have shortcomings in estimating those for non-polar aromatic compounds. To investigate a cause of error, we employed a novel systematic framework of quantum-mechanical/molecular-mechanical (QM/MM) coupling protocol in explicit solvation manner, termed DFT-CES, based on the grid-based mean-field treatment. With the aid of DFT-CES, we delved into multiple energy parts, thereby comparing DFT-CES and PB models component-by-component. By applying the modified PB model to estimate the hydration free energies of non-polar solutes, we find a possibility to improve the predictability of PB models. We expect that this study could shed light on providing an accurate route to study the hydration thermodynamics for various solute compounds. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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20 pages, 2969 KiB  
Article
Polarizable ab initio QM/MM Study of the Reaction Mechanism of N-tert-Butyloxycarbonylation of Aniline in [EMIm][BF4]
by Erik Antonio Vázquez-Montelongo, José Enrique Vázquez-Cervantes and G. Andrés Cisneros
Molecules 2018, 23(11), 2830; https://doi.org/10.3390/molecules23112830 - 31 Oct 2018
Cited by 10 | Viewed by 4590
Abstract
N-t e r t-butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using [...] Read more.
N-t e r t-butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using a polarizable multipolar force field with long–range electrostatic corrections were used to optimize the minimum energy paths (MEPs) associated with various possible reaction mechanisms employing the nudged elastic band (NEB) and the quadratic string method (QSM). The calculated reaction energies and energy barriers were compared with the corresponding gas-phase and dichloromethane results. Complementary Electron Localization Function (ELF)/NCI analyses provide insights on the critical structures along the MEP. The calculated results suggest the most likely path involves a sequential mechanism with the rate–limiting step corresponding to the nucleophilic attack of the aniline, followed by proton transfer and the release of CO 2 without the direct involvement of imidazolium cations as catalysts. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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25 pages, 416 KiB  
Article
A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes
by Gerhard König, Frank C. Pickard, Jing Huang, Walter Thiel, Alexander D. MacKerell, Bernard R. Brooks and Darrin M. York
Molecules 2018, 23(10), 2695; https://doi.org/10.3390/molecules23102695 - 19 Oct 2018
Cited by 28 | Viewed by 5609
Abstract
Maintaining a proper balance between specific intermolecular interactions and non-specific solvent interactions is of critical importance in molecular simulations, especially when predicting binding affinities or reaction rates in the condensed phase. The most rigorous metric for characterizing solvent affinity are solvation free energies, [...] Read more.
Maintaining a proper balance between specific intermolecular interactions and non-specific solvent interactions is of critical importance in molecular simulations, especially when predicting binding affinities or reaction rates in the condensed phase. The most rigorous metric for characterizing solvent affinity are solvation free energies, which correspond to a transfer from the gas phase into solution. Due to the drastic change of the electrostatic environment during this process, it is also a stringent test of polarization response in the model. Here, we employ both the CHARMM fixed charge and polarizable force fields to predict hydration free energies of twelve simple solutes. The resulting classical ensembles are then reweighted to obtain QM/MM hydration free energies using a variety of QM methods, including MP2, Hartree–Fock, density functional methods (BLYP, B3LYP, M06-2X) and semi-empirical methods (OM2 and AM1 ). Our simulations test the compatibility of quantum-mechanical methods with molecular-mechanical water models and solute Lennard–Jones parameters. In all cases, the resulting QM/MM hydration free energies were inferior to purely classical results, with the QM/MM Drude force field predictions being only marginally better than the QM/MM fixed charge results. In addition, the QM/MM results for different quantum methods are highly divergent, with almost inverted trends for polarizable and fixed charge water models. While this does not necessarily imply deficiencies in the QM models themselves, it underscores the need to develop consistent and balanced QM/MM interactions. Both the QM and the MM component of a QM/MM simulation have to match, in order to avoid artifacts due to biased solute–solvent interactions. Finally, we discuss strategies to improve the convergence and efficiency of multi-scale free energy simulations by automatically adapting the molecular-mechanics force field to the target quantum method. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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22 pages, 3362 KiB  
Article
Mapping Free Energy Pathways for ATP Hydrolysis in the E. coli ABC Transporter HlyB by the String Method
by Yan Zhou, Pedro Ojeda-May, Mulpuri Nagaraju, Bryant Kim and Jingzhi Pu
Molecules 2018, 23(10), 2652; https://doi.org/10.3390/molecules23102652 - 16 Oct 2018
Cited by 10 | Viewed by 4423
Abstract
HlyB functions as an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that enables bacteria to secrete toxins at the expense of ATP hydrolysis. Our previous work, based on potential energy profiles from combined quantum mechanical and molecular mechanical (QM/MM) calculations, has suggested that the [...] Read more.
HlyB functions as an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that enables bacteria to secrete toxins at the expense of ATP hydrolysis. Our previous work, based on potential energy profiles from combined quantum mechanical and molecular mechanical (QM/MM) calculations, has suggested that the highly conserved H-loop His residue H662 in the nucleotide binding domain (NBD) of E. coli HlyB may catalyze the hydrolysis of ATP through proton relay. To further test this hypothesis when entropic contributions are taken into account, we obtained QM/MM minimum free energy paths (MFEPs) for the HlyB reaction, making use of the string method in collective variables. The free energy profiles along the MFEPs confirm the direct participation of H662 in catalysis. The MFEP simulations of HlyB also reveal an intimate coupling between the chemical steps and a local protein conformational change involving the signature-loop residue S607, which may serve a catalytic role similar to an Arg-finger motif in many ATPases and GTPases in stabilizing the phosphoryl-transfer transition state. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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17 pages, 1346 KiB  
Article
Dual QM and MM Approach for Computing Equilibrium Isotope Fractionation Factor of Organic Species in Solution
by Meiyi Liu, Katelyn N. Youmans and Jiali Gao
Molecules 2018, 23(10), 2644; https://doi.org/10.3390/molecules23102644 - 15 Oct 2018
Cited by 3 | Viewed by 3881
Abstract
A dual QM and MM approach for computing equilibrium isotope effects has been described. In the first partition, the potential energy surface is represented by a combined quantum mechanical and molecular mechanical (QM/MM) method, in which a solute molecule is treated quantum mechanically, [...] Read more.
A dual QM and MM approach for computing equilibrium isotope effects has been described. In the first partition, the potential energy surface is represented by a combined quantum mechanical and molecular mechanical (QM/MM) method, in which a solute molecule is treated quantum mechanically, and the remaining solvent molecules are approximated classically by molecular mechanics. In the second QM/MM partition, differential nuclear quantum effects responsible for the isotope effect are determined by a statistical mechanical double-averaging formalism, in which the nuclear centroid distribution is sampled classically by Newtonian molecular dynamics and the quantum mechanical spread of quantized particles about the centroid positions is treated using the path integral (PI) method. These partitions allow the potential energy surface to be properly represented such that the solute part is free of nuclear quantum effects for nuclear quantum mechanical simulations, and the double-averaging approach has the advantage of sampling efficiency for solvent configuration and for path integral convergence. Importantly, computational precision is achieved through free energy perturbation (FEP) theory to alchemically mutate one isotope into another. The PI-FEP approach is applied to model systems for the 18O enrichment found in cellulose of trees to determine the isotope enrichment factor of carbonyl compounds in water. The present method may be useful as a general tool for studying isotope fractionation in biological and geochemical systems. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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12 pages, 1972 KiB  
Article
Carotenoid-Chlorophyll Interactions in a Photosynthetic Antenna Protein: A Supramolecular QM/MM Approach
by Matthew J. Guberman-Pfeffer and José A. Gascón
Molecules 2018, 23(10), 2589; https://doi.org/10.3390/molecules23102589 - 10 Oct 2018
Cited by 8 | Viewed by 3378
Abstract
Multichromophoric interactions control the initial events of energy capture and transfer in the light harvesting peridinin-chlorophyll a protein (PCP) from marine algae dinoflagellates. Due to the van der Waals association of the carotenoid peridinin (Per) with chlorophyll a in a unique 4:1 stoichiometric [...] Read more.
Multichromophoric interactions control the initial events of energy capture and transfer in the light harvesting peridinin-chlorophyll a protein (PCP) from marine algae dinoflagellates. Due to the van der Waals association of the carotenoid peridinin (Per) with chlorophyll a in a unique 4:1 stoichiometric ratio, supramolecular quantum mechanical/molecular mechanical (QM/MM) calculations are essential to accurately describe structure, spectroscopy, and electronic coupling. We show that, by enabling inter-chromophore electronic coupling, substantial effects arise in the nature of the transition dipole moment and the absorption spectrum. We further hypothesize that inter-protein domain Per-Per interactions are not negligible, and are needed to explain the experimental reconstruction features of the spectrum in wild-type PCP. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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16 pages, 1225 KiB  
Article
Representation of the QM Subsystem for Long-Range Electrostatic Interaction in Non-Periodic Ab Initio QM/MM Calculations
by Xiaoliang Pan, Edina Rosta and Yihan Shao
Molecules 2018, 23(10), 2500; https://doi.org/10.3390/molecules23102500 - 29 Sep 2018
Cited by 8 | Viewed by 3229
Abstract
In QM/MM calculations, it is essential to handle electrostatic interactions between the QM and MM subsystems accurately and efficiently. To achieve maximal efficiency, it is convenient to adopt a hybrid scheme, where the QM electron density is used explicitly in the evaluation of [...] Read more.
In QM/MM calculations, it is essential to handle electrostatic interactions between the QM and MM subsystems accurately and efficiently. To achieve maximal efficiency, it is convenient to adopt a hybrid scheme, where the QM electron density is used explicitly in the evaluation of short-range QM/MM electrostatic interactions, while a multipolar representation for the QM electron density is employed to account for the long-range QM/MM electrostatic interactions. In order to avoid energy discontinuity at the cutoffs, which separate the short- and long-range QM/MM electrostatic interactions, a switching function should be utilized to ensure a smooth potential energy surface. In this study, we benchmarked the accuracy of such hybrid embedding schemes for QM/MM electrostatic interactions using different multipolar representations, switching functions and cutoff distances. For test systems (neutral and anionic oxyluciferin in MM (aqueous and enzyme) environments), the best accuracy was acquired with a combination of QM electrostatic potential (ESP) charges and dipoles and two switching functions (long-range electrostatic corrections (LREC) and Switch) in the treatment of long-range QM/MM electrostatics. It allowed us to apply a 10Å distance cutoff and still obtain QM/MM electrostatics/polarization energies within 0.1 kcal/mol and time-dependent density functional theory (TDDFT)/MM vertical excitation energies within 10−3 eV from theoretical reference values. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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16 pages, 993 KiB  
Article
Efficient Computation of Free Energy Surfaces of Diels–Alder Reactions in Explicit Solvent at Ab Initio QM/MM Level
by Pengfei Li, Fengjiao Liu, Xiangyu Jia, Yihan Shao, Wenxin Hu, Jun Zheng and Ye Mei
Molecules 2018, 23(10), 2487; https://doi.org/10.3390/molecules23102487 - 28 Sep 2018
Cited by 10 | Viewed by 3700
Abstract
For Diels–Alder (DA) reactions in solution, an accurate and converged free energy (FE) surface at ab initio (ai) quantum mechanical/molecular mechanical (QM/MM) level is imperative for the understanding of reaction mechanism. However, this computation is still far too expensive. In a [...] Read more.
For Diels–Alder (DA) reactions in solution, an accurate and converged free energy (FE) surface at ab initio (ai) quantum mechanical/molecular mechanical (QM/MM) level is imperative for the understanding of reaction mechanism. However, this computation is still far too expensive. In a previous work, we proposed a new method termed MBAR+wTP, with which the computation of the ai FE profile can be accelerated by several orders of magnitude via a three-step procedure: (I) an umbrella sampling (US) using a semi-empirical (SE) QM/MM Hamiltonian is performed; (II) the FE profile is generated using the Multistate Bennett Acceptance Ratio (MBAR) analysis; and (III) a weighted Thermodynamic Perturbation (wTP) from the SE Hamiltonian to the ai Hamiltonian is performed to obtain the ai QM/MM FE profile using weight factors from the MBAR analysis. In this work, this method is extended to the calculations of two-dimensional FE surfaces of two Diels–Alder reactions of cyclopentadiene with either acrylonitrile or 1-4-naphthoquinone at ai QM/MM level. The accurate activation free energies at the ai QM/MM level, which are much closer to the experimental measurements than those calculated by other methods, indicate that this MBAR+wTP method can be applied in the studies of complex reactions in condensed phase with much-enhanced efficiency. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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12 pages, 1505 KiB  
Article
Do Better Quality Embedding Potentials Accelerate the Convergence of QM/MM Models? The Case of Solvated Acid Clusters
by Junming Ho, Yihan Shao and Jin Kato
Molecules 2018, 23(10), 2466; https://doi.org/10.3390/molecules23102466 - 26 Sep 2018
Cited by 13 | Viewed by 4087
Abstract
This study examines whether the use of more accurate embedding potentials improves the convergence of quantum mechanics/molecular mechanics (QM/MM) models with respect to the size of the QM region. In conjunction with density functional theory calculations using the ωB97X-D functional, various embedding potentials [...] Read more.
This study examines whether the use of more accurate embedding potentials improves the convergence of quantum mechanics/molecular mechanics (QM/MM) models with respect to the size of the QM region. In conjunction with density functional theory calculations using the ωB97X-D functional, various embedding potentials including the TIP3P water model, the effective fragment potential (EFP), and semi-empirical methods (PM6, PM7, and DFTB) were used to simulate the deprotonation energies of solvated acid clusters. The calculations were performed on solvated neutral (HA) and cationic (HB+) acids clusters containing 160 and 480 water molecules using configurations sampled from molecular dynamics simulations. Consistently, the ωB97X-D/EFP model performed the best when using a minimal QM region size. The performance for the other potentials appears to be highly sensitive to the charge character of the acid/base pair. Neutral acids display the expected trend that semi-empirical methods generally perform better than TIP3P; however, an opposite trend was observed for the cationic acids. Additionally, electronic embedding provided an improvement over mechanical embedding for the cationic systems, but not the neutral acids. For the best performing ωB97X-D/EFP model, a QM region containing about 6% of the total number of solvent molecules is needed to approach within 10 kJ mol−1 of the pure QM result if the QM region was chosen based on the distance from the reaction centre. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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16 pages, 1762 KiB  
Article
An Ab Initio QM/MM Study of the Electrostatic Contribution to Catalysis in the Active Site of Ketosteroid Isomerase
by Xianwei Wang and Xiao He
Molecules 2018, 23(10), 2410; https://doi.org/10.3390/molecules23102410 - 20 Sep 2018
Cited by 12 | Viewed by 3251
Abstract
The electric field in the hydrogen-bond network of the active site of ketosteroid isomerase (KSI) has been experimentally measured using vibrational Stark effect (VSE) spectroscopy, and utilized to study the electrostatic contribution to catalysis. A large gap was found in the electric field [...] Read more.
The electric field in the hydrogen-bond network of the active site of ketosteroid isomerase (KSI) has been experimentally measured using vibrational Stark effect (VSE) spectroscopy, and utilized to study the electrostatic contribution to catalysis. A large gap was found in the electric field between the computational simulation based on the Amber force field and the experimental measurement. In this work, quantum mechanical (QM) calculations of the electric field were performed using an ab initio QM/MM molecular dynamics (MD) simulation and electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method. Our results demonstrate that the QM-derived electric field based on the snapshots from QM/MM MD simulation could give quantitative agreement with the experiment. The accurate calculation of the electric field inside the protein requires both the rigorous sampling of configurations, and a QM description of the electrostatic field. Based on the direct QM calculation of the electric field, we theoretically confirmed that there is a linear correlation relationship between the activation free energy and the electric field in the active site of wild-type KSI and its mutants (namely, D103N, Y16S, and D103L). Our study presents a computational protocol for the accurate simulation of the electric field in the active site of the protein, and provides a theoretical foundation that supports the link between electric fields and enzyme catalysis. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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14 pages, 5467 KiB  
Article
Exploring Peptide–Solvent Interactions: A Computational Study
by Nadia Elghobashi-Meinhardt
Molecules 2018, 23(9), 2355; https://doi.org/10.3390/molecules23092355 - 14 Sep 2018
Cited by 1 | Viewed by 3127
Abstract
The dilemma of reconciling the contradictory evidence regarding the conformation of long solvated peptide chains is the so-called “reconciliation problem”. Clues regarding the stability of certain conformations likely lie in the electronic structure at the peptide–solvent interface, but the peptide–solvent interaction is not [...] Read more.
The dilemma of reconciling the contradictory evidence regarding the conformation of long solvated peptide chains is the so-called “reconciliation problem”. Clues regarding the stability of certain conformations likely lie in the electronic structure at the peptide–solvent interface, but the peptide–solvent interaction is not fully understood. Here, we study the influence of aqueous solvent on peptide conformations by using classical molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) energy calculations. The model systems include an 11-residue peptide, X 2 A 7 O 2 (XAO), where X, A, and O denote diaminobutyric acid, alanine, and ornithine, respectively, and a 9-mer (Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys). Spectroscopic and MD data present conflicting evidence regarding the structure of XAO in water; some results indicate that XAO adopts a polyproline II (P II ) conformation, whereas other findings suggest that XAO explores a range of conformations. To investigate this contradiction, we present here the results of MD simulations of XAO and the 9-mer in aqueous solution, combined with QM/MM energy calculations. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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16 pages, 3319 KiB  
Article
Adaptive QM/MM for Molecular Dynamics Simulations: 5. On the Energy-Conserved Permuted Adaptive-Partitioning Schemes
by Adam W. Duster, Chun-Hung Wang and Hai Lin
Molecules 2018, 23(9), 2170; https://doi.org/10.3390/molecules23092170 - 28 Aug 2018
Cited by 18 | Viewed by 3551
Abstract
In combined quantum-mechanical/molecular-mechanical (QM/MM) dynamics simulations, the adaptive-partitioning (AP) schemes reclassify atoms on-the-fly as QM or MM in a smooth manner. This yields a mobile QM subsystem with contents that are continuously updated as needed. Here, we tailor the Hamiltonian adaptive many-body correction [...] Read more.
In combined quantum-mechanical/molecular-mechanical (QM/MM) dynamics simulations, the adaptive-partitioning (AP) schemes reclassify atoms on-the-fly as QM or MM in a smooth manner. This yields a mobile QM subsystem with contents that are continuously updated as needed. Here, we tailor the Hamiltonian adaptive many-body correction (HAMBC) proposed by Boreboom et al. [J. Chem. Theory Comput. 2016, 12, 3441] to the permuted AP (PAP) scheme. The treatments lead to the HAMBC-PAP method (HPAP), which both conserves energy and produces accurate solvation structures in the test of “water-in-water” model system. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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15 pages, 2501 KiB  
Article
Improvement of Performance, Stability and Continuity by Modified Size-Consistent Multipartitioning Quantum Mechanical/Molecular Mechanical Method
by Hiroshi C. Watanabe
Molecules 2018, 23(8), 1882; https://doi.org/10.3390/molecules23081882 - 27 Jul 2018
Cited by 13 | Viewed by 3111
Abstract
For condensed systems, the incorporation of quantum chemical solvent effects into molecular dynamics simulations has been a major concern. To this end, quantum mechanical/molecular mechanical (QM/MM) techniques are popular and powerful options to treat gigantic systems. However, they cannot be directly applied because [...] Read more.
For condensed systems, the incorporation of quantum chemical solvent effects into molecular dynamics simulations has been a major concern. To this end, quantum mechanical/molecular mechanical (QM/MM) techniques are popular and powerful options to treat gigantic systems. However, they cannot be directly applied because of temporal and spatial discontinuity problems. To overcome these problems, in a previous study, we proposed a corrective QM/MM method, size-consistent multipartitioning (SCMP) QM/MM and successfully demonstrated that, using SCMP, it is possible to perform stable molecular dynamics simulations by effectively taking into account solvent quantum chemical effects. The SCMP method is characterized by two original features: size-consistency of a QM region among all QM/MM partitioning and partitioning update. However, in our previous study, the performance was not fully elicited compared to the theoretical upper bound and the optimal partitioning update protocol and parameters were not fully verified. To elicit the potential performance, in the present study, we simplified the theoretical framework and modified the partitioning protocol. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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12 pages, 2728 KiB  
Article
Orientation of Laurdan in Phospholipid Bilayers Influences Its Fluorescence: Quantum Mechanics and Classical Molecular Dynamics Study
by Mirza Wasif Baig, Marek Pederzoli, Piotr Jurkiewicz, Lukasz Cwiklik and Jiri Pittner
Molecules 2018, 23(7), 1707; https://doi.org/10.3390/molecules23071707 - 13 Jul 2018
Cited by 17 | Viewed by 4844
Abstract
Fluidity of lipid membranes is known to play an important role in the functioning of living organisms. The fluorescent probe Laurdan embedded in a lipid membrane is typically used to assess the fluidity state of lipid bilayers by utilizing the sensitivity of Laurdan [...] Read more.
Fluidity of lipid membranes is known to play an important role in the functioning of living organisms. The fluorescent probe Laurdan embedded in a lipid membrane is typically used to assess the fluidity state of lipid bilayers by utilizing the sensitivity of Laurdan emission to the properties of its lipid environment. In particular, Laurdan fluorescence is sensitive to gel vs liquid–crystalline phases of lipids, which is demonstrated in different emission of the dye in these two phases. Still, the exact mechanism of the environment effects on Laurdan emission is not understood. Herein, we utilize dipalmitoylphosphatidylcholine (DPPC) and dioleoylphosphatidylcholine (DOPC) lipid bilayers, which at room temperature represent gel and liquid–crystalline phases, respectively. We simulate absorption and emission spectra of Laurdan in both DOPC and DPPC bilayers with quantum chemical and classical molecular dynamics methods. We demonstrate that Laurdan is incorporated in heterogeneous fashion in both DOPC and DPPC bilayers, and that its fluorescence depends on the details of this embedding. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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12 pages, 794 KiB  
Article
Parametrization of Combined Quantum Mechanical and Molecular Mechanical Methods: Bond-Tuned Link Atoms
by Xin-Ping Wu, Laura Gagliardi and Donald G. Truhlar
Molecules 2018, 23(6), 1309; https://doi.org/10.3390/molecules23061309 - 30 May 2018
Cited by 10 | Viewed by 4531
Abstract
Combined quantum mechanical and molecular mechanical (QM/MM) methods are the most powerful available methods for high-level treatments of subsystems of very large systems. The treatment of the QM−MM boundary strongly affects the accuracy of QM/MM calculations. For QM/MM calculations having covalent bonds cut [...] Read more.
Combined quantum mechanical and molecular mechanical (QM/MM) methods are the most powerful available methods for high-level treatments of subsystems of very large systems. The treatment of the QM−MM boundary strongly affects the accuracy of QM/MM calculations. For QM/MM calculations having covalent bonds cut by the QM−MM boundary, it has been proposed previously to use a scheme with system-specific tuned fluorine link atoms. Here, we propose a broadly parametrized scheme where the parameters of the tuned F link atoms depend only on the type of bond being cut. In the proposed new scheme, the F link atom is tuned for systems with a certain type of cut bond at the QM−MM boundary instead of for a specific target system, and the resulting link atoms are call bond-tuned link atoms. In principle, the bond-tuned link atoms can be as convenient as the popular H link atoms, and they are especially well adapted for high-throughput and accurate QM/MM calculations. Here, we present the parameters for several kinds of cut bonds along with a set of validation calculations that confirm that the proposed bond-tuned link-atom scheme can be as accurate as the system-specific tuned F link-atom scheme. Full article
(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations)
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