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Special Issue "Computer Simulation on Membrane Receptors and Lipid Bilayers"

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).

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
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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://www.mdpi.com/journal/ijms/special_issues/Membrane_Receptors), we can focus on a larger group of molecular systems:

  1. Membrane receptors, which mediate signal transduction for cellular responses to extracellular stimuli in their native cellular membranes.
  2. Supramolecular interacting systems composed by small peptides, endogenous ligands and/or drugs and the lipid bilayers of the cellular membrane.
  3. 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

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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. 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 (4 papers)

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Research

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Open AccessArticle
Novel Positive Allosteric Modulators of µ Opioid Receptor—Insight from In Silico and In Vivo Studies
Int. J. Mol. Sci. 2020, 21(22), 8463; https://doi.org/10.3390/ijms21228463 - 11 Nov 2020
Viewed by 376
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 [...] Read more.
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)
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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
Int. J. Mol. Sci. 2020, 21(19), 7064; https://doi.org/10.3390/ijms21197064 - 25 Sep 2020
Viewed by 540
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 [...] Read more.
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)
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Open AccessArticle
Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study
Int. J. Mol. Sci. 2020, 21(18), 6693; https://doi.org/10.3390/ijms21186693 - 12 Sep 2020
Cited by 1 | Viewed by 884
Abstract
The histamine H2 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 [...] Read more.
The histamine H2 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-Gs complex based on the structure of the ternary complex of the β2-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-Gs 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 μs-timescale in the ternary histamine-H2R-Gs complex and in a truncated complex that contains only Gs helix α5 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)
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Review

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Open AccessReview
How Do Molecular Dynamics Data Complement Static Structural Data of GPCRs
Int. J. Mol. Sci. 2020, 21(16), 5933; https://doi.org/10.3390/ijms21165933 - 18 Aug 2020
Cited by 3 | Viewed by 994
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 [...] Read more.
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)
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