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TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.

ABSTRACT: Classical molecular dynamics (MD) simulations based on atomic models play an increasingly important role in a wide range of applications in physics, biology, and chemistry. Nonetheless, generating genuine knowledge about biological systems using MD simulations remains challenging. Protein tyrosine kinases are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Due to the large conformational changes and long timescales involved in their function, these kinases present particularly challenging problems to modern computational and theoretical frameworks aimed at elucidating the dynamics of complex biomolecular systems. Markov state models have achieved limited success in tackling the broader conformational ensemble and biased methods are often employed to examine specific long timescale events. Recent advances in machine learning continue to push the limitations of current methodologies and provide notable improvements when integrated with the existing frameworks. A broad perspective is drawn from a critical review of recent studies.

SUBMITTER: Thomas T

PROVIDER: S-EPMC9749240 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.

Thomas Trayder T Roux Benoît B

The European physical journal. B 20211011 10

Classical molecular dynamics (MD) simulations based on atomic models play an increasingly important role in a wide range of applications in physics, biology, and chemistry. Nonetheless, generating genuine knowledge about biological systems using MD simulations remains challenging. Protein tyrosine kinases are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Due to the large conformational changes and long timescales involv ...[more]

PMID: 36524055

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Project description:Gleevec, a well-known cancer therapeutic agent, is an effective inhibitor of several tyrosine kinases, including Abl and c-Kit, but displays less potency to inhibit closely homologous tyrosine kinases, such as Lck and c-Src. Because many structural features of the binding site are highly conserved in these homologous kinases, the molecular determinants responsible for the binding specificity of Gleevec remain poorly understood. To address this issue, free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent was used to compute the binding affinity of Gleevec to Abl, c-Kit, Lck, and c-Src. The results of the FEP/MD calculations are in good agreement with experiments, enabling a detailed and quantitative dissection of the absolute binding free energy in terms of various thermodynamic contributions affecting the binding specificity of Gleevec to the kinases. Dominant binding free energy contributions arises from the van der Waals dispersive interaction, compensating about two-thirds of the unfavorable free energy penalty associated with the loss of translational, rotational, and conformational freedom of the ligand upon binding. In contrast, the contributions from electrostatic and repulsive interactions nearly cancel out due to solvent effects. Furthermore, the calculations show the importance of the conformation of the kinase activation loop. Among the kinases examined, Abl provides the most favorable binding environment for Gleevec via optimal protein-ligand interactions and a small free energy cost for loss of the translational, rotational, and conformational freedom upon ligand binding. The FEP/MD calculations additionally reveal that Lck and c-Src provide similar nonbinding interactions with the bound-Gleevec, but the former pays less entropic penalty for the ligand losing its translational, rotational, and conformational motions to bind, examining the empirically observed differential binding affinities of Gleevec between the two Src-family kinases.

Dataset Information

TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.

Publications

TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.

Similar Datasets

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