Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Computer Simulation on Membrane Receptors and Lipid Bilayers

Special Issue Editors
Special Issue Information
Keywords
Published Papers

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 (28 February 2021) | Viewed by 17213

Share This Special Issue

Special Issue Editor

Prof. Dr. Roberta Galeazzi

E-Mail Website
Guest Editor

Department of Life and Environmental Science (DISVA), Marche Polythecnic University, Ancona, Italy
Interests: computer aided drug design; molecular dynamics simulation of membrane receptors and lipid bilayers; rational drug design; bacterial efflux pumps' inhibitors; computational design of novel nanovectors for drug delivery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Computational techniques have developed successful in silico approaches to reproduce with high accuracy the dynamical and physical-chemical properties of supramolecular systems involving lipid bilayers. In this Special Issue, as a continuum of our previous one (https://0-www-mdpi-com.brum.beds.ac.uk/journal/ijms/special_issues/Membrane_Receptors), we can focus on a larger group of molecular systems:

Membrane receptors, which mediate signal transduction for cellular responses to extracellular stimuli in their native cellular membranes.
Supramolecular interacting systems composed by small peptides, endogenous ligands and/or drugs and the lipid bilayers of the cellular membrane.
Nanovectors such as liposomes or other lipid-based vectors as Drug or Gene Delivery agents.

Here we want to cover all types of in silico simulation aimed at elucidating the structure and the function of these supramolecular systems. In addition, studies related to a rational drug design approach with a membrane receptor as target are welcome.

Potential topics include, without being limited to, the following:

Molecular dynamics simulation of ion channels or GPCRs receptors
Computer aided drug design targeted to membrane receptors
Ligand–receptor dynamics
Function and structure of membrane receptors
Coarse grained molecular dynamics of receptor association and oligomerization
Lipid bilayers molecular dynamics simulations
Design in silico of novel liposomal vectors for Drug Design
RNA or DNA interactions with cellular membranes or lipid-based nanovectors

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

Membrane receptors
Molecular dynamics
Molecular docking
Protein–protein association
Rational drug design

Published Papers (5 papers)

Download All Papers

Research

Jump to: Review

12 pages, 20357 KiB

Open AccessArticle

Effect of Ions and Sequence Variants on the Antagonist Binding Properties of the Histamine H₁ Receptor

by Marcus Conrad, Christian A. Söldner and Heinrich Sticht

Int. J. Mol. Sci. 2022, 23(3), 1420; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031420 - 26 Jan 2022

Cited by 3 | Viewed by 2296

Abstract

The histamine H₁ receptor (H₁R) is a G protein-coupled receptor (GPCR) and represents a main target in the treatment of allergic reactions as well as inflammatory reactions and depressions. Although the overall effect of antagonists on H₁ function has been extensively investigated, rather little is known about the potential modulatory effect of ions or sequence variants on antagonist binding. We investigated the dynamics of a phosphate ion present in the crystal structure and of a sodium ion, for which we determined the position in the allosteric pocket by metadynamics simulations. Both types of ions exhibit significant dynamics within their binding site; however, some key contacts remain stable over the simulation time, which might be exploited to develop more potent drugs targeting these sites. The dynamics of the ions is almost unaffected by the presence or absence of doxepin, as also reflected in their small effect (less than 1 kcal·mol⁻¹) on doxepin binding affinity. We also examined the effect of four H₁R sequence variants observed in the human population on doxepin binding. These variants cause a reduction in doxepin affinity of up to 2.5 kcal·mol⁻¹, indicating that personalized medical treatments that take into account individual mutation patterns could increase precision in the dosage of GPCR-targeting drugs. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

► Show Figures

Figure 1

15 pages, 5481 KiB

Open AccessArticle

Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies

by Damian Bartuzi, Ewa Kędzierska, Agnieszka A. Kaczor, Helmut Schmidhammer and Dariusz Matosiuk

Int. J. Mol. Sci. 2020, 21(22), 8463; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228463 - 11 Nov 2020

Cited by 9 | Viewed by 2105

Abstract

Opioids are the drugs of choice in severe pain management. Unfortunately, their use involves serious, potentially lethal side effects. Therefore, efforts in opioid drug design turn toward safer and more effective mechanisms, including allosteric modulation. In this study, molecular dynamics simulations in silico and ‘writhing’ tests in vivo were used to characterize potential allosteric mechanism of two previously reported compounds. The results suggest that investigated compounds bind to μ opioid receptor in an allosteric site, augmenting action of morphine at subeffective doses, and exerting antinociceptive effect alone at higher doses. Detailed analysis of in silico calculations suggests that first of the compounds behaves more like allosteric agonist, while the second compound acts mainly as a positive allosteric modulator. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

► Show Figures

Graphical abstract

18 pages, 4011 KiB

Open AccessArticle

Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations

by Jingjing Feng, Yan Zhang, Quhuan Li, Ying Fang and Jianhua Wu

Int. J. Mol. Sci. 2020, 21(19), 7064; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197064 - 25 Sep 2020

Cited by 6 | Viewed by 2085

Abstract

The PSGL-1-actin cytoskeleton linker proteins ezrin/radixin/moesin (ERM), an adaptor between P-selectin glycoprotein ligand-1 (PSGL-1) and spleen tyrosine kinase (Syk), is a key player in PSGL-1 signal, which mediates the adhesion and recruitment of leukocytes to the activated endothelial cells in flow. Binding of PSGL-1 to ERM initials intracellular signaling through inducing phosphorylation of Syk, but effects of tensile force on unligation and phosphorylation site exposure of ERM bound with PSGL-1 remains unclear. To answer this question, we performed a series of so-called “ramp-clamp” steered molecular dynamics (SMD) simulations on the radixin protein FERM domain of ERM bound with intracellular juxtamembrane PSGL-1 peptide. The results showed that, the rupture force of complex pulled with constant velocity was over 250 pN, which prevented the complex from breaking in front of pull-induced exposure of phosphorylation site on immunoreceptor tyrosine activation motif (ITAM)-like motif of ERM; the stretched complex structure under constant tensile forces <100 pN maintained on a stable quasi-equilibrium state, showing a high mechano-stabilization of the clamped complex; and, in consistent with the force-induced allostery at clamped stage, increasing tensile force (<50 pN) would decrease the complex dissociation probability but facilitate the phosphorylation site exposure, suggesting a force-enhanced biophysical connectivity of PSGL-1 signaling. These force-enhanced characters in both phosphorylation and unligation of ERM bound with PSGL-1 should be mediated by a catch-slip bond transition mechanism, in which four residue interactions on binding site were involved. This study might provide a novel insight into the transmembrane PSGL-1 signal, its biophysical connectivity and molecular structural basis for cellular immune responses in mechano-microenvironment, and showed a rational SMD-based computer strategy for predicting structure-function relation of protein under loads. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

► Show Figures

Figure 1

18 pages, 9537 KiB

Open AccessArticle

Agonist Binding and G Protein Coupling in Histamine H₂ Receptor: A Molecular Dynamics Study

by Marcus Conrad, Christian A. Söldner, Yinglong Miao and Heinrich Sticht

Int. J. Mol. Sci. 2020, 21(18), 6693; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186693 - 12 Sep 2020

Cited by 10 | Viewed by 4653

Abstract

The histamine H

_{2}

The histamine H

_{2}

receptor (H₂R) plays an important role in the regulation of gastric acid secretion. Therefore, it is a main drug target for the treatment of gastroesophageal reflux or peptic ulcer disease. However, there is as of yet no 3D-structural information available hampering a mechanistic understanding of H₂R. Therefore, we created a model of the histamine-H₂R-G_s complex based on the structure of the ternary complex of the

β_{2}

-adrenoceptor and investigated the conformational stability of this active GPCR conformation. Since the physiologically relevant motions with respect to ligand binding and conformational changes of GPCRs can only partly be assessed on the timescale of conventional MD (cMD) simulations, we also applied metadynamics and Gaussian accelerated molecular dynamics (GaMD) simulations. A multiple walker metadynamics simulation in combination with cMD was applied for the determination of the histamine binding mode. The preferential binding pose detected is in good agreement with previous data from site directed mutagenesis and provides a basis for rational ligand design. Inspection of the H₂R-G_s interface reveals a network of polar interactions that may contribute to H₂R coupling selectivity. The cMD and GaMD simulations demonstrate that the active conformation is retained on a

μ

s-timescale in the ternary histamine-H₂R-G_s complex and in a truncated complex that contains only G_s helix

α

5 instead of the entire G protein. In contrast, histamine alone is unable to stabilize the active conformation, which is in line with previous studies of other GPCRs. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

► Show Figures

Figure 1

Review

Jump to: Research

26 pages, 2750 KiB

Open AccessReview

How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs

by Mariona Torrens-Fontanals, Tomasz Maciej Stepniewski, David Aranda-García, Adrián Morales-Pastor, Brian Medel-Lacruz and Jana Selent

Int. J. Mol. Sci. 2020, 21(16), 5933; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165933 - 18 Aug 2020

Cited by 34 | Viewed by 5519

Abstract

G protein-coupled receptors (GPCRs) are implicated in nearly every physiological process in the human body and therefore represent an important drug targeting class. Advances in X-ray crystallography and cryo-electron microscopy (cryo-EM) have provided multiple static structures of GPCRs in complex with various signaling partners. However, GPCR functionality is largely determined by their flexibility and ability to transition between distinct structural conformations. Due to this dynamic nature, a static snapshot does not fully explain the complexity of GPCR signal transduction. Molecular dynamics (MD) simulations offer the opportunity to simulate the structural motions of biological processes at atomic resolution. Thus, this technique can incorporate the missing information on protein flexibility into experimentally solved structures. Here, we review the contribution of MD simulations to complement static structural data and to improve our understanding of GPCR physiology and pharmacology, as well as the challenges that still need to be overcome to reach the full potential of this technique. Full article

(This article belongs to the Special Issue Computer Simulation on Membrane Receptors and Lipid Bilayers)

► Show Figures