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Molecules
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Ligands and Conformational Changes in Receptors
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Ligands and Conformational Changes in Receptors

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

Deadline for manuscript submissions: closed (31 October 2024) | Viewed by 2481

Special Issue Editor

Dr. Meng Cui

E-Mail Website
Guest Editor
Bouvé College of Health Sciences, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA, USA
Interests: GPCR; ion channels; molecular dynamics simulations; structure based drug design; taste receptors

Special Issue Information

Dear Colleagues,

The past decade has seen significant advancements in the field of structural biology, particularly in the study of protein receptors, such as, G protein coupled receptors (GPCRs). The use of crystallography and cryo-electron microscopy has allowed us to determine atomic resolution three-dimensional structures, which has revolutionized our understanding of the function properties of these proteins. Additionally, advancements in computing power have enabled researchers to study the activation of protein receptors by their corresponding ligands, a critical step in their functional roles.

This special issue invites colleagues who are interested in protein receptor function studies regulated by ligands using experimental or computational approaches to contribute original research or review articles. The topics of interest include, but are not limited to, receptor-ligand complex structure determination using NMR, crystallography, and cryo-electron microscopy, molecular dynamics simulations on receptor activation by ligands, exploring dynamic interactions between receptors and ligands, receptor structure-based drug discovery, and computational and experimental studies on ligand-receptor interactions.

We welcome contributions that utilize innovative approaches to shed light on the mechanisms involved in activating protein receptors by their corresponding ligands, with the ultimate goal of contributing to the development of novel therapeutic interventions.

Dr. Meng Cui
Guest Editor

Manuscript Submission Information

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. 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

  • receptor-ligand interactions
  • protein dynamics
  • structure-based drug discovery
  • molecular dynamics simulations
  • GPCRs
  • molecular basis of receptor activation

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Published Papers (2 papers)

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Research

18 pages, 4745 KiB  
Article
Molecular Dynamics (MD) Simulations Provide Insights into the Activation Mechanisms of 5-HT2A Receptors
by Meng Cui, Yongcheng Lu, Mihaly Mezei and Diomedes E. Logothetis
Molecules 2024, 29(20), 4935; https://doi.org/10.3390/molecules29204935 - 18 Oct 2024
Viewed by 932
Abstract
Recent breakthroughs in the determination of atomic resolution 3-D cryo-electron microscopy structures of membrane proteins present an unprecedented opportunity for drug discovery. Structure-based drug discovery utilizing in silico methods enables the study of dynamic connectivity of stable conformations induced by the drug in [...] Read more.
Recent breakthroughs in the determination of atomic resolution 3-D cryo-electron microscopy structures of membrane proteins present an unprecedented opportunity for drug discovery. Structure-based drug discovery utilizing in silico methods enables the study of dynamic connectivity of stable conformations induced by the drug in achieving its effect. With the ever-expanding computational power, simulations of this type reveal protein dynamics in the nano-, micro-, and even millisecond time scales. In the present study, aiming to characterize the protein dynamics of the 5HT2A receptor stimulated by ligands (agonist/antagonist), we performed 1 µs MD simulations on 5HT2A/DOI (agonist), 5HT2A/GSK215083 (antagonist), and 5HT2A (APO, no ligand) systems. The crystal structure of 5HT2A/zotepine (antagonist) (PDB: 6A94) was used to set up the simulation systems in a lipid bilayer environment. We found the monitoring of the ionic lock residue pair (R3.50-E6.30) of 5HT2A in MD simulations to be a good approximation of the effects of agonists (ionic lock breakage) or antagonists (ionic lock formation) on receptor activation. We further performed analyses of the MD trajectories, including Principal Component Analysis (PCA), hydrogen bond, salt bridge, and hydrophobic interaction network analyses, and correlation between residues to identify key elements of receptor activation. Our results suggest that in order to trigger receptor activation, DOI must interact with 5HT2A through residues V5.39, G5.42, S5.43, and S5.46 on TM5, inducing significant conformational changes in the backbone angles of G5.42 and S5.43. DOI also interacted with residues W6.48 (toggle switch) and F6.51 on TM6, causing major conformational shifts in the backbone angles of F6.44 and V6.45. These structural changes were transmitted to the intracellular ends of TM5, TM6, and ICL3, resulting in the breaking of the ionic lock and subsequent G protein activation. The studies could be helpful in future design of selective agonists/antagonists for various serotonin receptors (5HT1A, 5HT2A, 5HT2B, 5HT2C, and 5HT7) involved in detrimental disorders, such as addiction and schizophrenia. Full article
(This article belongs to the Special Issue Ligands and Conformational Changes in Receptors)
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31 pages, 12355 KiB  
Article
Three-Dimensional Interaction Homology: Deconstructing Residue–Residue and Residue–Lipid Interactions in Membrane Proteins
by Glen E. Kellogg
Molecules 2024, 29(12), 2838; https://doi.org/10.3390/molecules29122838 - 14 Jun 2024
Viewed by 834
Abstract
A method is described to deconstruct the network of hydropathic interactions within and between a protein’s sidechain and its environment into residue-based three-dimensional maps. These maps encode favorable and unfavorable hydrophobic and polar interactions, in terms of spatial positions for optimal interactions, relative [...] Read more.
A method is described to deconstruct the network of hydropathic interactions within and between a protein’s sidechain and its environment into residue-based three-dimensional maps. These maps encode favorable and unfavorable hydrophobic and polar interactions, in terms of spatial positions for optimal interactions, relative interaction strength, as well as character. In addition, these maps are backbone angle-dependent. After map calculation and clustering, a finite number of unique residue sidechain interaction maps exist for each backbone conformation, with the number related to the residue’s size and interaction complexity. Structures for soluble proteins (~749,000 residues) and membrane proteins (~387,000 residues) were analyzed, with the latter group being subdivided into three subsets related to the residue’s position in the membrane protein: soluble domain, core-facing transmembrane domain, and lipid-facing transmembrane domain. This work suggests that maps representing residue types and their backbone conformation can be reassembled to optimize the medium-to-high resolution details of a protein structure. In particular, the information encoded in maps constructed from the lipid-facing transmembrane residues appears to paint a clear picture of the protein–lipid interactions that are difficult to obtain experimentally. Full article
(This article belongs to the Special Issue Ligands and Conformational Changes in Receptors)
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