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Computational Approaches for the Investigation of Complex Molecular Mechanisms

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Informatics".

Deadline for manuscript submissions: closed (10 January 2023) | Viewed by 21618

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Dr. Renata Tisi

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Department of Biotechnology and Biosciences, University of Milano-Bicocca, P.za della Scienza 2, 20126 Milan, Italy
Interests: signal transduction; calcium; molecular modeling; molecular dynamics; docking; mathematical modeling
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Dear Colleagues,

In recent years, technical and scientifical progress in computational science has provided valuable and affordable tools for scientific research in the field of molecular biology. From bioinformatics to molecular modeling, from the -omics approach to the development of mathematical models, computational biomodeling has provided relevant contributions to the clarification of fundamental biological mechanisms.

For this Special Issue, we would like to invite papers that address the following concepts:

Integrated approach between wet and in silico techniques to tackle a relevant biological issue;
Exploitation of computational models to direct wet research;
Computational approach applied to gain novel interpretation of previous experimental data.

Suggested methodologies include, but are not limited to, bioinformatics, homology modelling, analysis of gene expression to identify transcriptional regulation pathways, protein–protein and ligand–protein docking, molecular dynamics, mathematical modeling, and molecular or cell biology techniques (not mandatory).

Dr. Renata Tisi
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

signal transduction
transcriptional regulation
molecular modeling
molecular dynamics
molecular docking
system biology
mathematical modeling
meta-analysis

Published Papers (11 papers)

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Research

18 pages, 6486 KiB

Open AccessArticle

An Integrative Approach to Investigate the Mode of Action of (−)-Dendroparishiol in Bacterial Meningitis: Computer-Aided Estimation of Biological Activity and Network Pharmacology

by Thanchanok Limcharoen, Peththa Wadu Dasuni Wasana, Hasriadi, Pornpoom Angsuwattana, Chawanphat Muangnoi, Sakan Warinhomhoun, Tassanee Ongtanasup, Boonchoo Sritularak, Opa Vajragupta, Pornchai Rojsitthisak and Pasarapa Towiwat

Int. J. Mol. Sci. 2023, 24(9), 8072; https://doi.org/10.3390/ijms24098072 - 29 Apr 2023

Cited by 1 | Viewed by 2027

Abstract

Bacterial meningitis remains one of the most prevalent infectious diseases worldwide. Although advances in medical care have improved mortality and morbidity, neurological complications remain high. Therefore, aside from antibiotics, therapeutic adjuvants targeting neuroinflammation are essential to combat the long-term neuronal sequelae of bacterial meningitis. In the present study, we propose (−)-dendroparishiol as a potential add-on therapy to improve neuroinflammation associated with bacterial meningitis. The biological activity of (−)-dendroparishiol was first predicted by computational analysis and further confirmed in vitro using a cell-based assay with LPS-induced BV-2 microglial cells. Biological pathways involved with (−)-dendroparishiol were identified by applying network pharmacology. Computational predictions of biological activity indicated possible attenuation of several inflammatory processes by (−)-dendroparishiol. In LPS-induced BV-2 microglial cells, (−)-dendroparishiol significantly reduced the expression of inflammatory mediators: iNOS, NO, COX-2, IL-6, and TNF-α. Molecular docking results demonstrated the potential iNOS and COX-2 inhibitory activity of (−)-dendroparishiol. Network pharmacological analysis indicated the plausible role of (−)-dendroparishiol in biological processes involved in oxidative stress and neuroinflammation with enrichment in neuroinflammatory pathways. Overall, this study provides scientific evidence for the potential application of (−)-dendroparishiol in the management of bacterial meningitis-associated neuroinflammation. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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15 pages, 4945 KiB

Open AccessArticle

Structural Characterization of Hypoxia Inducible Factor α—Prolyl Hydroxylase Domain 2 Interaction through MD Simulations

by Giorgia F. Camagni, Giovanni Minervini and Silvio C. E. Tosatto

Int. J. Mol. Sci. 2023, 24(5), 4710; https://doi.org/10.3390/ijms24054710 - 1 Mar 2023

Viewed by 1796

Abstract

The Prolyl Hydroxylases (PHDs) are an enzymatic family that regulates cell oxygen-sensing. PHDs hydroxylate hypoxia-inducible transcription factors α (HIFs-α) driving their proteasomal degradation. Hypoxia inhibits PHDs activity, inducing HIFs-α stabilization and cell adaptation to hypoxia. As a hallmark of cancer, hypoxia promotes neo-angiogenesis and cell proliferation. PHD isoforms are thought to have a variable impact on tumor progression. All isoforms hydroxylate HIF-α (HIF-1,2,3α) with different affinities. However, what determines these differences and how they pair with tumor growth is poorly understood. Here, molecular dynamics simulations were used to characterize the PHD2 binding properties in complexes with HIF-1α and HIF-2α. In parallel, conservation analysis and binding free energy calculations were performed to better understand PHD2 substrate affinity. Our data suggest a direct association between the PHD2 C-terminus and HIF-2α that is not observed in the PHD2/HIF-1α complex. Furthermore, our results indicate that phosphorylation of a PHD2 residue, Thr405, causes a variation in binding energy, despite the fact that this PTM has only a limited structural impact on PHD2/HIFs-α complexes. Collectively, our findings suggest that the PHD2 C-terminus may act as a molecular regulator of PHD’s activity. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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17 pages, 6411 KiB

Open AccessArticle

Interaction of Tryptophan- and Arginine-Rich Antimicrobial Peptide with E. coli Outer Membrane—A Molecular Simulation Approach

by George Necula, Mihaela Bacalum and Mihai Radu

Int. J. Mol. Sci. 2023, 24(3), 2005; https://doi.org/10.3390/ijms24032005 - 19 Jan 2023

Cited by 8 | Viewed by 1899

Abstract

A short antimicrobial peptide (AMP), rich in tryptophan and arginine (P6—HRWWRWWRR-NH2), was used in molecular dynamics (MD) simulations to investigate the interaction between AMPs and lipopolysaccharides (LPS) from two E. coli outer membrane (OM) membrane models. The OM of Gram-negative bacteria is an asymmetric bilayer, with the outer layer consisting exclusively of lipopolysaccharide molecules and the lower leaflet made up of phospholipids. The mechanisms by which short AMPs permeate the OM of Gram-negative bacteria are not well understood at the moment. For this study, two types of E. coli OM membrane models were built with (i) smooth LPS composed of lipid A, K12 core and O21 O-antigen, and (ii) rough type LPS composed of lipid A and R1 core. An OmpF monomer from E. coli was embedded in both membrane models. MD trajectories revealed that AMP insertion in the LPS layer was facilitated by the OmpF-created gap and allowed AMPs to form hydrogen bonds with the phosphate groups of inner core oligosaccharides. OM proteins such as OmpF may be essential for the permeation of short AMPs such as P6 by exposing the LPS binding site or even by direct translocation of AMPs across the OM. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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24 pages, 5373 KiB

Open AccessArticle

Functional Heterodimerization between the G Protein-Coupled Receptor GPR17 and the Chemokine Receptors 2 and 4: New Evidence

by Simona Daniele, Simona Saporiti, Stefano Capaldi, Deborah Pietrobono, Lara Russo, Uliano Guerrini, Tommaso Laurenzi, Elham Ataie Kachoie, Luca Palazzolo, Vincenzo Russo, Maria Pia Abbracchio, Ivano Eberini and Maria Letizia Trincavelli

Int. J. Mol. Sci. 2023, 24(1), 261; https://doi.org/10.3390/ijms24010261 - 23 Dec 2022

Cited by 1 | Viewed by 2016

Abstract

GPR17, a G protein-coupled receptor, is a pivotal regulator of myelination. Its endogenous ligands trigger receptor desensitization and downregulation allowing oligodendrocyte terminal maturation. In addition to its endogenous agonists, GPR17 could be promiscuously activated by pro-inflammatory oxysterols and chemokines released at demyelinating lesions. Herein, the chemokine receptors CXCR2 and CXCR4 were selected to perform both in silico modelling and in vitro experiments to establish their structural and functional interactions with GPR17. The relative propensity of GPR17 and CXCR2 or CXCR4 to form homo- and hetero-dimers was assessed by homology modelling and molecular dynamics (MD) simulations, and co-immunoprecipitation and immunoenzymatic assay. The interaction between chemokine receptors and GPR17 was investigated by determining receptor-mediated modulation of intracellular cyclic adenosine monophosphate (cAMP). Our data show the GPR17 association with CXCR2 or CXCR4 and the negative regulation of these interactions by CXCR agonists or antagonists. Moreover, GPR17 and CXCR2 heterodimers can functionally influence each other. In contrast, CXCR4 can influence GPR17 functionality, but not vice versa. According to MD simulations, all the dimers reached conformational stability and negative formation energy, confirming the experimental observations. The cross-talk between these receptors could play a role in the development of the neuroinflammatory milieu associated with demyelinating events. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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16 pages, 2699 KiB

Open AccessArticle

Novel Morpholine-Bearing Quinoline Derivatives as Potential Cholinesterase Inhibitors: The Influence of Amine, Carbon Linkers and Phenylamino Groups

by Cheng Liu, Li-Ning Wang and Yu-Ming Liu

Int. J. Mol. Sci. 2022, 23(19), 11231; https://doi.org/10.3390/ijms231911231 - 23 Sep 2022

Cited by 3 | Viewed by 1505

Abstract

A series of novel 4-N-phenylaminoquinoline derivatives containing a morpholine group were designed and synthesized, and their anti-cholinesterase activities and ABTS radical-scavenging activities were tested. Among them, compounds 11a, 11g, 11h, 11j, 11l, and 12a had comparable inhibition activities to reference galantamine in AChE. Especially, compound 11g revealed the most potent inhibition on AChE and BChE with IC₅₀ values of 1.94 ± 0.13 μM and 28.37 ± 1.85 μM, respectively. The kinetic analysis demonstrated that both the compounds 11a and 11g acted as mixed-type AChE inhibitors. A further docking comparison between the 11a- and 12a-AChE complexes agreed with the different inhibitory potency observed in experiments. Besides, compounds 11f and 11l showed excellent ABTS radical-scavenging activities, with IC₅₀ values of 9.07 ± 1.34 μM and 6.05 ± 1.17 μM, respectively, which were superior to the control, Trolox (IC₅₀ = 11.03 ± 0.76 μM). It is worth noting that 3-aminoquinoline derivatives 12a–12d exhibited better drug-like properties. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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22 pages, 8703 KiB

Open AccessArticle

Towards Molecular Understanding of the Functional Role of UbiJ-UbiK₂ Complex in Ubiquinone Biosynthesis by Multiscale Molecular Modelling Studies

by Romain Launay, Elin Teppa, Carla Martins, Sophie S. Abby, Fabien Pierrel, Isabelle André and Jérémy Esque

Int. J. Mol. Sci. 2022, 23(18), 10323; https://doi.org/10.3390/ijms231810323 - 7 Sep 2022

Cited by 4 | Viewed by 1952

Abstract

Ubiquinone (UQ) is a polyisoprenoid lipid found in the membranes of bacteria and eukaryotes. UQ has important roles, notably in respiratory metabolisms which sustain cellular bioenergetics. Most steps of UQ biosynthesis take place in the cytosol of E. coli within a multiprotein complex called the Ubi metabolon, that contains five enzymes and two accessory proteins, UbiJ and UbiK. The SCP2 domain of UbiJ was proposed to bind the hydrophobic polyisoprenoid tail of UQ biosynthetic intermediates in the Ubi metabolon. How the newly synthesised UQ might be released in the membrane is currently unknown. In this paper, we focused on better understanding the role of the UbiJ-UbiK₂ heterotrimer forming part of the metabolon. Given the difficulties to gain functional insights using biophysical techniques, we applied a multiscale molecular modelling approach to study the UbiJ-UbiK₂ heterotrimer. Our data show that UbiJ-UbiK₂ interacts closely with the membrane and suggests possible pathways to enable the release of UQ into the membrane. This study highlights the UbiJ-UbiK₂ complex as the likely interface between the membrane and the enzymes of the Ubi metabolon and supports that the heterotrimer is key to the biosynthesis of UQ₈ and its release into the membrane of E. coli. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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15 pages, 3658 KiB

Open AccessArticle

Depolarizing Effects in Hydrogen Bond Energy in 3₁₀-Helices Revealed by Quantum Chemical Analysis

by Hiroko X. Kondo, Haruki Nakamura and Yu Takano

Int. J. Mol. Sci. 2022, 23(16), 9032; https://doi.org/10.3390/ijms23169032 - 12 Aug 2022

Cited by 4 | Viewed by 1331

Abstract

Hydrogen-bond (H-bond) energies in 3₁₀-helices of short alanine peptides were systematically examined by precise DFT calculations with the negative fragmentation approach (NFA), a modified method based on the molecular tailoring approach. The contribution of each H-bond was evaluated in detail from the 3₁₀-helical conformation of total energies (whole helical model, WH_3-10 model), and the results were compared with the property of H-bond in α-helix from our previous study. The H-bond energies of the WH_3-10 model exhibited tendencies different from those exhibited by the α-helix in that they depended on the helical position of the relevant H-bond pair. H-bond pairs adjacent to the terminal H-bond pairs were observed to be strongly destabilized. The analysis of electronic structures indicated that structural characteristics cause the destabilization of the H-bond in 3₁₀-helices. We also found that the longer the helix length, the more stable the H-bond in the terminal pairs of the WH_3-10 model, suggesting the action of H-bond cooperativity. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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14 pages, 3956 KiB

Open AccessArticle

A Computational–Experimental Investigation of the Molecular Mechanism of Interleukin-6-Piperine Interaction

by Ana Paula Ribeiro Povinelli, Gabriel Zazeri, Alan M. Jones and Marinônio Lopes Cornélio

Int. J. Mol. Sci. 2022, 23(14), 7994; https://doi.org/10.3390/ijms23147994 - 20 Jul 2022

Cited by 4 | Viewed by 1792

Abstract

Herein, we elucidate the biophysical aspects of the interaction of an important protein, Interleukin-6 (IL6), which is involved in cytokine storm syndrome, with a natural product with anti-inflammatory activity, piperine. Despite the role of piperine in the inhibition of the transcriptional protein NF-κB pathway responsible for activation of IL6 gene expression, there are no studies to the best of our knowledge regarding the characterisation of the molecular interaction of the IL6-piperine complex. In this context, the characterisation was performed with spectroscopic experiments aided by molecular modelling. Fluorescence spectroscopy alongside van’t Hoff analyses showed that the complexation event is a spontaneous process driven by non-specific interactions. Circular dichroism aided by molecular dynamics revealed that piperine caused local α-helix reduction. Molecular docking and molecular dynamics disclosed the microenvironment of interaction as non-polar amino acid residues. Although piperine has three available hydrogen bond acceptors, only one hydrogen-bond was formed during our simulation experiments, reinforcing the major role of non-specific interactions that we observed experimentally. Root mean square deviation (RMSD) and hydrodynamic radii revealed that the IL6-piperine complex was stable during 800 ns of simulation. Taken together, these results can support ongoing IL6 drug discovery efforts. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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11 pages, 1970 KiB

Open AccessArticle

Molecular Dynamics Simulations Reveal Structural Interconnections within Sec14-PH Bipartite Domain from Human Neurofibromin

by Fabio Rizza, Jacopo Vertemara and Renata Tisi

Int. J. Mol. Sci. 2022, 23(10), 5707; https://doi.org/10.3390/ijms23105707 - 20 May 2022

Viewed by 1485

Abstract

Neurofibromin, the main RasGAP in the nervous system, is a 2818 aa protein with several poorly characterized functional domains. Mutations in the NF1-encoding gene lead to an autosomal dominant syndrome, neurofibromatosis, with an incidence of 1 out of 3000 newborns. Missense mutations spread in the Sec14-PH-encoding sequences as well. Structural data could not highlight the defect in mutant Sec14-PH functionality. By performing molecular dynamics simulations at different temperatures, we found that the lid-lock is fundamental for the structural interdependence of the NF1 bipartite Sec14-PH domain. In fact, increased flexibility in the lid-lock loop, observed for the K1750Δ mutant, leads to disconnection of the two subdomains and can affect the stability of the Sec14 subdomain. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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17 pages, 3774 KiB

Open AccessArticle

Intramolecular Interaction with the E6 Region Stabilizes the Closed Conformation of the N-SH2 Domain and Concurs with the Self-Inhibitory Docking in Downregulating the Activity of the SHP2 Tyrosine Phosphatase: A Molecular Dynamics Study

by Emanuele Bellacchio

Int. J. Mol. Sci. 2022, 23(9), 4794; https://doi.org/10.3390/ijms23094794 - 27 Apr 2022

Cited by 1 | Viewed by 2622

Abstract

The localization and activity of the SHP2 tyrosine phosphatase across different cellular compartments to the target substrates are steered by the binding of phosphotyrosine (pY) peptides to the tandem SH2 domains. The most N-terminal domain (N-SH2) can also keep the enzyme inactive by intramolecular occlusion of the catalytic site. Enzyme activity can be recovered by an allosteric disruption of this self-inhibitory docking upon the binding of pY peptides to the N-SH2 domain. Prior to this, the N-SH2 domain must abandon the closed conformation because it impedes the access of pY peptides to the binding cleft. Although it cooperates with the self-inhibitory docking in the negative regulation of the phosphatase activity, the structural determinants of the stability of the closed conformation in the self-inhibited phosphatase are still elusive. To address this issue, a molecular dynamics simulation study is carried out. It is shown that the closed conformation is stabilized by the interaction of the N-SH2 domain with a conserved peptide portion in the region encoded by PTPN11 exon 6 (E6). Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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12 pages, 3574 KiB

Open AccessArticle

Prodrug-Based Targeting Approach for Inflammatory Bowel Diseases Therapy: Mechanistic Study of Phospholipid-Linker-Cyclosporine PLA₂-Mediated Activation

by Milica Markovic, Karina Abramov-Harpaz, Clil Regev, Shimon Ben-Shabat, Aaron Aponick, Ellen M. Zimmermann, Yifat Miller and Arik Dahan

Int. J. Mol. Sci. 2022, 23(5), 2673; https://doi.org/10.3390/ijms23052673 - 28 Feb 2022

Cited by 5 | Viewed by 1853

Abstract

Therapeutics with activity specifically at the inflamed sites throughout the gastrointestinal tract (GIT) would be a major advance in our therapeutic approach to inflammatory bowel disease (IBD). We aimed to develop the prodrug approach that can allow such site-specific drug delivery. Currently, using cyclosporine as a drug of choice in IBD is limited to the most severe cases due to substantial systemic toxicities and narrow therapeutic index of this drug. Previously, we synthesized a series of a phospholipid-linker-cyclosporine (PLC) prodrugs designed to exploit the overexpression of phospholipase A₂ (PLA₂) in the inflamed intestinal tissues, as the prodrug-activating enzyme. Nevertheless, the extent and rate of prodrug activation differed significantly. In this study we applied in-vitro and modern in-silico tools based on molecular dynamics (MD) simulation, to gain insight into the dynamics and mechanisms of the PLC prodrug activation. We aimed to elucidate the reason for the significant activation change between different linker lengths in our prodrug design. Our work reveals that the PLC conjugate with the 12-carbon linker length yields the optimal prodrug activation by PLA₂ in comparison to shorter linker length (6-carbons). This optimized length efficiently allows cyclosporine to be released from the prodrug to the active pocket of PLA₂. This newly developed mechanistic approach, presented in this study, can be applied for future prodrug optimization to accomplish optimal prodrug activation and drug targeting in various conditions that include overexpression of PLA₂. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms)

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