arXiv subjects

Daria B. Kokh

Publications and source records attributed to Daria B. Kokh.

3 recordsLinked to original sources

arXiv2021

Brownian Dynamics Simulations of Proteins in the Presence of Surfaces: Long-range Electrostatics and Mean-field Hydrodynamics

Simulations of macromolecular diffusion and adsorption in confined environments can offer valuable mechanistic insights into numerous biophysical processes. In order to model solutes at atomic detail on relevant time scales, Brownian Dynamics simulations can be carried out with the approximation of rigid body solutes moving through a continuum solvent. This allows the precomputation of interaction potential grids for the solutes, thereby allowing the computationally efficient calculation of forces. However, hydrodynamic and long-range electrostatic interactions cannot be fully treated with grid-based approaches alone. Here, we develop a treatment of both hydrodynamic and electrostatic interactions to include the presence of surfaces by modeling grid-based and long-range interactions. We describe its application to simulate the self-association and many-molecule adsorption of the well-characterized protein Hen Egg-White Lysozyme to mica-like and silica-like surfaces. We find that the computational model can recover a number of experimental observables of the adsorption process and provide insights into their determinants. The computational model is implemented in the Simulation of Diffusional Association (SDA) software package.

cond-mat.soft↗

arXiv2020

Ligand unbinding mechanisms and kinetics for T4 lysozyme mutants from tauRAMD simulations

The protein-ligand residence time, tau, influences molecular function in biological networks and has been recognized as an important determinant of drug efficacy. To predict tau, computational methods must overcome the problem that tau often exceeds the timescales accessible to conventional molecular dynamics (MD) simulation. Here, we apply the tau-Random Acceleration Molecular Dynamics (tauRAMD) method to a set of kinetically characterized complexes of T4 lysozyme mutants with engineered binding cavities. tauRAMD yields relative ligand dissociation rates in good accordance with experiments and thereby allows a comprehensive characterization of the ligand egress routes and determinants of tau. Although ligand dissociation by multiple egress routes is observed, we find that egress via the predominant route determines the value of tau. We also find that the presence of metastable states along egress pathways slows down protein-ligand dissociation. These physical insights could be exploited in the rational optimization of the kinetic properties of drug candidates.

q-bio.QM↗

arXiv2020

Recent progress in molecular simulation methods for drug binding kinetics

Due to the contribution of drug-target binding kinetics to drug efficacy, there is a high level of interest in developing methods to predict drug-target binding kinetic parameters. During the review period, a wide range of enhanced sampling molecular dynamics simulation-based methods has been developed for computing drug-target binding kinetics and studying binding and unbinding mechanisms. Here, we assess the performance of these methods considering two benchmark systems in detail: mutant T4 lysozyme-ligand complexes and a large set of N-HSP90-inhibitor complexes. The results indicate that some of the simulation methods can already be usefully applied in drug discovery or lead optimization programs but that further studies on more high-quality experimental benchmark datasets are necessary to improve and validate computational methods.

q-bio.QM↗