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Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

ABSTRACT: This study presents a novel computational approach to study molecular recognition and binding kinetics for drug-like compounds dissociating from a flexible protein system. The intermediates and their free energy profile during ligand association and dissociation processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. The method applied the milestoning theory to extract kinetics and thermodynamics information from running short classical molecular dynamics (MD) simulations for frames from a given dissociation path. High-dimensional ligand-protein motions (3N-6 degrees of freedom) during ligand dissociation were reduced by use of principal component modes for assigning more than 100 milestones, and classical MD runs were allowed to travel multiple milestones to efficiently obtain ensemble distribution of initial structures for MD simulations and estimate the transition time and rate during ligand traveling between milestones. We used five pyrazolourea ligands and cyclin-dependent kinase 8 with cyclin C (CDK8/CycC) as our model system as well as metadynamics and a pathway search method to sample dissociation pathways. With our strategy, we constructed the free energy profile for highly mobile biomolecular systems. The computed binding free energy and residence time correctly ranked the pyrazolourea ligand series, in agreement with experimental data. Guided by a barrier of a ligand passing an ?C helix and activation loop, we introduced one hydroxyl group to parent compounds to design our ligands with increased residence time and validated our prediction by experiments. This work provides a novel and robust approach to investigate dissociation kinetics of large and flexible systems for understanding unbinding mechanisms and designing new small-molecule drugs with desired binding kinetics.

SUBMITTER: Tang Z

PROVIDER: S-EPMC7809013 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

Tang Zhiye Z Chen Si-Han SH Chang Chia-En A CA

Journal of chemical theory and computation 20200220 3

This study presents a novel computational approach to study molecular recognition and binding kinetics for drug-like compounds dissociating from a flexible protein system. The intermediates and their free energy profile during ligand association and dissociation processes control ligand-protein binding kinetics and bring a more complete picture of ligand-protein binding. The method applied the milestoning theory to extract kinetics and thermodynamics information from running short classical mole ...[more]

PMID: 32031801

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Project description:Understanding the interaction of ligands with biomolecules is an integral component of drug discovery and development. Challenges for computing thermodynamic and kinetic quantities for pharmaceutically relevant receptor-ligand complexes include the size and flexibility of the ligands, large-scale conformational rearrangements of the receptor, accurate force field parameters, simulation efficiency, and sufficient sampling associated with rare events. Our recently developed multiscale milestoning simulation approach, SEEKR2 (Simulation Enabled Estimation of Kinetic Rates v.2), has demonstrated success in predicting unbinding (koff) kinetics by employing molecular dynamics (MD) simulations in regions closer to the binding site. The MD region is further subdivided into smaller Voronoi tessellations to improve the simulation efficiency and parallelization. To date, all MD simulations are run using general molecular mechanics (MM) force fields. The accuracy of calculations can be further improved by incorporating quantum mechanical (QM) methods into generating system-specific force fields through reparameterizing ligand partial charges in the bound state. The force field reparameterization process modifies the potential energy landscape of the bimolecular complex, enabling a more accurate representation of the intermolecular interactions and polarization effects at the bound state. We present QMrebind (Quantum Mechanical force field reparameterization at the receptor-ligand binding site), an ORCA-based software that facilitates reparameterizing the potential energy function within the phase space representing the bound state in a receptor-ligand complex. With SEEKR2 koff estimates and experimentally determined kinetic rates, we compare and interpret the receptor-ligand unbinding kinetics obtained using the newly reparameterized force fields for model host-guest systems and HSP90-inhibitor complexes. This method provides an opportunity to achieve higher accuracy in predicting receptor-ligand koff rate constants.

Dataset Information

Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

Publications

Transient States and Barriers from Molecular Simulations and the Milestoning Theory: Kinetics in Ligand-Protein Recognition and Compound Design.

Similar Datasets

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