+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Decoding the Role of Water Dynamics in Ligand-Protein Unbinding: CRF1R as a Test Case

Decoding the Role of Water Dynamics in Ligand-Protein Unbinding: CRF1R as a Test Case

Journal of Chemical Information and Modeling 55(9): 1857-1866

The residence time of a ligand-protein complex is a crucial aspect in determining biological effect in vivo. Despite its importance, the prediction of ligand koff still remains challenging for modern computational chemistry. We have developed aMetaD, a fast and generally applicable computational protocol to predict ligand-protein unbinding events using a molecular dynamics (MD) method based on adiabatic-bias MD and metadynamics. This physics-based, fully flexible, and pose-dependent ligand scoring function evaluates the maximum energy (RTscore) required to move the ligand from the bound-state energy basin to the next. Unbinding trajectories are automatically analyzed and translated into atomic solvation factor (SF) values representing the water dynamics during the unbinding event. This novel computational protocol was initially tested on two M3 muscarinic receptor and two adenosine A2A receptor antagonists and then evaluated on a test set of 12 CRF1R ligands. The resulting RTscores were used successfully to classify ligands with different residence times. Additionally, the SF analysis was used to detect key differences in the degree of accessibility to water molecules during the predicted ligand unbinding events. The protocol provides actionable working hypotheses that are applicable in a drug discovery program for the rational optimization of ligand binding kinetics.

(PDF emailed within 0-6 h: $19.90)

Accession: 057563395

Download citation: RISBibTeXText

PMID: 26335976

DOI: 10.1021/acs.jcim.5b00440

Related references

Impact of Surface Water Layers on Protein--Ligand Binding: How Well Are Experimental Data Reproduced by Molecular Dynamics Simulations in a Thermolysin Test Case?. Journal of Chemical Information and Modeling 56(1): 223-233, 2016

Role of water and steric constraints in the kinetics of cavity-ligand unbinding. Proceedings of the National Academy of Sciences of the United States of America 112(39): 12015-9, 2016

Towards Achieving Efficient and Accurate Ligand-Protein Unbinding with Deep Learning and Molecular Dynamics through RAVE. Journal of Chemical Theory and Computation 2018, 2018

Multiple copy and Random Expulsion Molecular Dynamics as tools for exploring protein-ligand binding and unbinding. Abstracts of Papers American Chemical Society 223(1-2): COMP 38, 2002

Steered Molecular Dynamics for Studying Ligand Unbinding of Ecdysone Receptor. Journal of Biomolecular Structure & Dynamics: 1-28, 2017

Ligand unbinding pathways from the vitamin D receptor studied by molecular dynamics simulations. European Biophysics Journal 38(2): 185-198, 2008

Water movement during ligand unbinding from receptor site. Biophysical Journal 87(1): 121-128, 2004

Molecular dynamics force probe simulations of antibody/antigen unbinding: entropic control and nonadditivity of unbinding forces. Biophysical Journal 81(3): 1295-1313, 2001

MoMA-LigPath: a web server to simulate protein-ligand unbinding. Nucleic Acids Research 41(Web Server Issue): W297-W302, 2013

Computational Study of Protein-Ligand Unbinding for Enzyme Engineering. Frontiers in Chemistry 6: 650-650, 2019

Protein Structural Memory Influences Ligand Binding Mode(s) and Unbinding Rates. Journal of Chemical Theory and Computation 12(3): 1393-1399, 2016

Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps. Proceedings of the National Academy of Sciences of the United States of America 112(5): E386-E391, 2015

The molecular mechanism of ligand unbinding from the human telomeric G-quadruplex by steered molecular dynamics and umbrella sampling simulations. Physical Chemistry Chemical Physics 17(19): 12857-12869, 2016

Specific Unbinding Forces Between Mutated Human P-Selectin Glycoprotein Ligand-1 and Viral Protein-1 Measured Using Force Spectroscopy. Journal of Physical Chemistry Letters 8(21): 5290-5295, 2017

Multiple Ligand Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore. Biophysical Journal 112(4): 620-629, 2017