scholarly journals BDflex: A method for efficient treatment of molecular flexibility in calculating protein-ligand binding rate constants from Brownian dynamics simulations

2012 ◽  
Vol 137 (13) ◽  
pp. 135105 ◽  
Author(s):  
Nicholas Greives ◽  
Huan-Xiang Zhou
Keyword(s):  
Ligand Binding ◽  
Rate Constants ◽  
Brownian Dynamics ◽  
Molecular Flexibility ◽  
Efficient Treatment ◽  
Binding Rate ◽  
Dynamics Simulations ◽  
Brownian Dynamics Simulations

scholarly journals A multiscale approach for computing gated ligand binding from molecular dynamics and Brownian dynamics simulations

2021 ◽  
Author(s):  
S. Kashif Sadiq ◽  
Abraham Muñiz Chicharro ◽  
Patrick Friedrich ◽  
Rebecca C. Wade
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Rate Constants ◽  
Brownian Dynamics ◽  
Multiscale Approach ◽  
Wide Range ◽  
Conformational Gating ◽  
Dynamics Simulations ◽  
Brownian Dynamics Simulations ◽  
Hiv 1

We develop an approach to characterise the effects of gating by a multi-conformation protein consisting of macrostate conformations that are either accessible or inaccessible to ligand binding. We first construct a Markov state model of the apo-protein from atomistic molecular dynamics simulations from which we identify macrostates and their conformations, compute their relative macrostate populations and interchange kinetics, and structurally characterise them in terms of ligand accessibility. We insert the calculated first-order rate constants for conformational transitions into a multi-state gating theory from which we derive a gating factor γ that quantifies the degree of conformational gating. Applied to HIV-1 protease, our approach yields a kinetic network of three accessible (semi-open, open and wide-open) and two inaccessible (closed and a newly identified, `parted') macrostate conformations. The `parted' conformation sterically partitions the active site, suggesting a possible role in product release. We find that the binding kinetics of drugs and drug-like inhibitors to HIV-1 protease falls in the slow gating regime. However, because γ=0.75, conformational gating only modestly slows ligand binding. Brownian dynamics simulations of the diffusional association of eight inhibitors to the protease - that have a wide range of experimental association constants (~104 - 1010 M-1s-1) - yields gated rate constants in the range ~0.5-5.7 × 108 M-1s-1. This indicates that, whereas the association rate of some inhibitors is described by the model, for most inhibitors the subsequent induced fit step leads to slower association rates. For systems known to be modulated by conformational gating, the approach could be scaled computationally efficiently to screen association kinetics for a large number of ligands.

scholarly journals Ligand Binding Rate Constants in Heme Proteins Using Markov State Models and Molecular Dynamics Simulations

ChemPhysChem ◽  
2019 ◽  
Vol 20 (19) ◽  
pp. 2451-2460
Author(s):  
Mauro Bringas ◽  
Leandro E. Lombardi ◽  
F. Javier Luque ◽  
Darío A. Estrin ◽  
Luciana Capece
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Molecular Dynamics Simulations ◽  
Rate Constants ◽  
Heme Proteins ◽  
Markov State ◽  
Markov State Models ◽  
Binding Rate ◽  
State Models ◽  
Dynamics Simulations
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