Biology subjects

Shahoei, R.

Publications and source records attributed to Shahoei, R..

3 recordsLinked to original sources

bioRxiv2026

Conformational Preference Classification of Integrin-Binding Ligands Using Free Energy Perturbation

Integrins are crucial cell adhesion receptors and attractive therapeutic targets, but developing safe small-molecule inhibitors has been challenging, at least in part due to inadvertent partial agonism caused by stabilization of the integrins open, high-affinity state. To address this challenge, we present a computational approach using Absolute Binding Free Energy Perturbation (AB-FEP) calculations to predict whether a ligand will stabilize the open or closed integrin states, leveraging the difference between the ligands binding free energy to the respective end states. Despite challenges posed by Ca and Mg ions, metal-coordinating residues in the binding pocket, and the subtlety of structural differences between states, AB-FEP achieved excellent classification performance on a set of known opening and closing ligands, significantly outperforming docking scores and MM-GBSA results. We also showed a good correlation between AB-FEP binding free energy differences and experimental values. Furthermore, AB-FEP provided insights into intermediate integrin states and analysis of simulation trajectories confirmed the formation of a water-mediated hydrogen bond network with an ion in the binding pocket to be characteristic for closing ligands. This work demonstrates AB-FEP as a robust method for classifying integrin ligands by the conformation they stabilize and for understanding their functional mechanisms, offering valuable guidance for designing safe and conformationally selective integrin therapeutics. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/721214v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1a0b8eforg.highwire.dtl.DTLVardef@cd6b56org.highwire.dtl.DTLVardef@420cc0org.highwire.dtl.DTLVardef@533963_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Mechanistic insights into ligand dissociation from the SARS-CoV-2 spike glycoprotein

The COVID-19 pandemic, driven by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spurred an urgent need for effective therapeutic interventions. The spike glycoprotein of the SARS-CoV-2 is crucial for infiltrating host cells, rendering it a key candidate for drug development. By interacting with the human angiotensin-converting enzyme 2 (ACE2) receptor, the spike initiates the infection of SARS-CoV-2. Linoleate is known to bind the spike glycoprotein, subsequently reducing its interaction with ACE2. However, the detailed kinetics underlying the protein-ligand interaction remains unclear. In this study, we characterized the pathways of ligand dissociation and the conformational changes associated with the spike glycoprotein by using ligand Gaussian accelerated molecular dynamics (LiGaMD). Our simulations resulted in eight complete ligand dissociation trajectories, unveiling two distinct ligand unbinding pathways. The preference between these two pathways depends on the gate distance between two -helices in the receptor binding domain (RBD) and the position of the N-linked glycan at N343. Our study also highlights the essential contributions of K417, N121 glycan, and N165 glycan in ligand unbinding, which are equally crucial in enhancing spike-ACE2 binding. We suggest that the presence of the ligand influences the motions of these residues and glycans, consequently reducing accessibility for spike-ACE2 binding. These findings enhance our understanding of ligand dissociation from the spike glycoprotein and offer significant implications for drug design strategies in the battle against COVID-19.

biophysics↗

bioRxiv2019

Mechanism of gating and partial agonist action in the glycine receptor

The glycine receptor is a pentameric, neurotransmitter-activated ion channel that transitions between closed/resting, open and desensitized states. Glycine, a full agonist, produces an open channel probability (Po) of [~]1.0 while partial agonists, such as taurine and {gamma}-amino butyric acid (GABA) yield submaximal Po values. Despite extensive studies of pentameric Cys-loop receptors, there is little knowledge of the molecular mechanisms underpinning partial agonist action and how the receptor transitions from the closed to open and to desensitized conformations. Here we use electrophysiology and molecular dynamics (MD) simulations, together with a large ensemble of single particle cryo-EM reconstructions, to show how agonists populate agonist-bound yet closed channel states, thus explaining their lesser efficacy, yet also populate agonist-bound open and desensitized states. Measurements within the neurotransmitter binding pocket, as a function of bound agonist, provide a metric to correlate the extent of agonist-induced conformational changes to open channel probability across the Cys-loop receptor family.

neuroscience↗