ArticleBiochemistry2018
Ligand Binding Pathways and Conformational Transitions of the HIV Protease.
Article in Biochemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- Mechanistic studies of small molecule ligands selective to RNA single G bulges.Nucleic acids research · 2025Article
- Pathway Specific Unbinding Free Energy Profiles of Ritonavir Dissociation from HIV-1 Protease.Biochemistry · 2025Article
- Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation.Nature communications · 2025Article
- Accelerating Molecular Dynamics Simulations for Drug Discovery.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Functionalized Fullerene Potentially Inhibits SARS-CoV-2 Infection by Modulating Spike Protein Conformational Changes.International journal of molecular sciences · 2023Article
- Unraveling the catalytic mechanism of SARS-CoV-2 papain-like protease with allosteric modulation of C270 mutation using multiscale computational approaches.Chemical science · 2023Article
- Predicting Biomolecular Binding Kinetics: A Review.Journal of chemical theory and computation · 2023Review
- Article
- Exact reaction coordinates for flap opening in HIV-1 protease.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Evolving Experimental Techniques for Structure-Based Drug Design.The journal of physical chemistry. B · 2022Review
- Gaussian Accelerated Molecular Dynamics Simulations Investigation on the Mechanism of Angiotensin-Converting Enzyme (ACE) C-Domain Inhibition by Dipeptides.Foods (Basel, Switzerland) · 2022Article
- Ritonavir and xk263 Binding-Unbinding with HIV-1 Protease: Pathways, Energy and Comparison.Life (Basel, Switzerland) · 2022Article
- Mechanism of RNA recognition by a Musashi RNA-binding protein.Current research in structural biology · 2022Review
- Molecular Modeling of ABHD5 Structure and Ligand Recognition.Frontiers in molecular biosciences · 2022Article
- Challenges and frontiers of computational modelling of biomolecular recognition.QRB discovery · 2022Article
- dockECR: Open consensus docking and ranking protocol for virtual screening of small molecules.Journal of molecular graphics & modelling · 2021Article
- Molecular dynamics of the viral life cycle: progress and prospects.Current opinion in virology · 2021Review
- Multiscale computational study of ligand binding pathways: Case of p38 MAP kinase and its inhibitors.Biophysical journal · 2021Article
- Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease.Nature communications · 2021Article
- Biomolecular Modeling and Simulation: A Prospering Multidisciplinary Field.Annual review of biophysics · 2021Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein-drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500-2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ∼5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug-receptor interactions for the HIV protease and by extension many other target proteins.
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