ArticleBiopolymers2016
Identifying binding hot spots on protein surfaces by mixed-solvent molecular dynamics: HIV-1 protease as a test case.
Article in Biopolymers, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Mixed-Solvent MD suite: modular tools for building and analyzing mixed-solvent molecular dynamics systems.Journal of computer-aided molecular design · 2026Article
- Exploring Binding Sites in Chagas Disease Protein TcP21 Using Integrated Mixed Solvent Molecular Dynamics Approaches.Journal of chemical information and modeling · 2025Article
- Watermelon: setup and validation of anJournal of enzyme inhibition and medicinal chemistry · 2024Article
- Enhancing SILCS-MC via GPU Acceleration and Ligand Conformational Optimization with Genetic and Parallel Tempering Algorithms.The journal of physical chemistry. B · 2024Article
- FASTDock: A Pipeline for Allosteric Drug Discovery.Journal of chemical information and modeling · 2023Article
- Fragment screening using biolayer interferometry reveals ligands targeting the SHP-motif binding site of the AAA+ ATPase p97.Communications chemistry · 2022Article
- Discovery of the Cryptic Sites of SARS-CoV-2 Papain-like Protease and Analysis of Its Druggability.International journal of molecular sciences · 2022Article
- Computational Identification of Possible Allosteric Sites and Modulators of the SARS-CoV-2 Main Protease.Journal of chemical information and modeling · 2022Article
- Application of Site-Identification by Ligand Competitive Saturation in Computer-Aided Drug Design.New journal of chemistry = Nouveau journal de chimie · 2022Article
- Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design.Frontiers in pharmacology · 2022Review
- Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction.ACS central science · 2021Article
- Chemical validation of a druggable site on Hsp27/HSPB1 using in silico solvent mapping and biophysical methods.Bioorganic & medicinal chemistry · 2021Article
- Pharmmaker: Pharmacophore modeling and hit identification based on druggability simulations.Protein science : a publication of the Protein Society · 2020Article
- Screening of Natural Products Targeting SARS-CoV-2-ACE2 Receptor Interface - A MixMD Based HTVS Pipeline.Frontiers in chemistry · 2020Article
- Free Energies and Entropies of Binding Sites Identified by MixMD Cosolvent Simulations.Journal of chemical information and modeling · 2019Article
- Deriving Ligand Orientation in Weak Protein-Ligand Complexes by DEEP-STD NMR Spectroscopy in the Absence of Protein Chemical-Shift Assignment.Chembiochem : a European journal of chemical biology · 2019Article
- Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.Journal of medicinal chemistry · 2018Article
- MixMD Probeview: Robust Binding Site Prediction from Cosolvent Simulations.Journal of chemical information and modeling · 2018Article
- re-TAMD: exploring interactions between H3 peptide and YEATS domain using enhanced sampling.BMC structural biology · 2018Article
- Predicting Displaceable Water Sites Using Mixed-Solvent Molecular Dynamics.Journal of chemical information and modeling · 2018Article
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Authors and funding
5 authors.
Funding
Abstract
Mixed-solvent molecular dynamics (MixMD) simulations use full protein flexibility and competition between water and small organic probes to achieve accurate hot-spot mapping on protein surfaces. In this study, we improved MixMD using human immunodeficiency virus type-1 protease (HIVp) as the test case. We used three probe-water solutions (acetonitrile-water, isopropanol-water, and pyrimidine-water), first at 50% w/w concentration and later at 5% v/v. Paradoxically, better mapping was achieved by using fewer probes; 5% simulations gave a superior signal-to-noise ratio and far fewer spurious hot spots than 50% MixMD. Furthermore, very intense and well-defined probe occupancies were observed in the catalytic site and potential allosteric sites that have been confirmed experimentally. The Eye site, an allosteric site underneath the flap of HIVp, has been confirmed by the presence of a 5-nitroindole fragment in a crystal structure. MixMD also mapped two additional hot spots: the Exo site (between the Gly16-Gly17 and Cys67-Gly68 loops) and the Face site (between Glu21-Ala22 and Val84-Ile85 loops). The Exo site was observed to overlap with crystallographic additives such as acetate and dimethyl sulfoxide that are present in different crystal forms of the protein. Analysis of crystal structures of HIVp in different symmetry groups has shown that some surface sites are common interfaces for crystal contacts, which means that they are surfaces that are relatively easy to desolvate and complement with organic molecules. MixMD should identify these sites; in fact, their occupancy values help establish a solid cut-off where "druggable" sites are required to have higher occupancies than the crystal-packing faces.
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