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Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.

ABSTRACT: Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimensional network with average connectivity of about 2.93, which is significantly higher than the connectivity for a one-dimensional reaction coordinate. The free energy barrier for Gleevec dissociation is estimated to be ∼10 kcal/mol, and the exit time is ∼55 ms. We examined the transition state conformations using both, the committor and transition function. We show that near the transition state the highly conserved salt bridge K217 and E286 is transiently broken. Together with the calculated free energy profile, these calculations can advance the understanding of the molecular interaction mechanisms between Gleevec and Abl kinase and play a role in future drug design and optimization studies.

SUBMITTER: Narayan B

PROVIDER: S-EPMC8192492 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.

Narayan Brajesh B Buchete Nicolae-Viorel NV Elber Ron R

The journal of physical chemistry. B 20210430 22

Gleevec (a.k.a., imatinib) is an important anticancer (e.g., chronic myeloid leukemia) chemotherapeutic drug due to its inhibitory interaction with the Abl kinase. Here, we use atomically detailed simulations within the Milestoning framework to study the molecular dissociation mechanism of Gleevec from Abl kinase. We compute the dissociation free energy profile, the mean first passage time for unbinding, and explore the transition state ensemble of conformations. The milestones form a multidimen ...[more]

PMID: 33930271

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Project description:BackgroundKinases are a family of enzymes that catalyze the transfer of the ɤ-phosphate group from ATP to a protein's residue. Malfunctioning kinases are involved in many health problems such as cardiovascular diseases, diabetes, and cancer. Kinases transitions between multiple conformations of inactive to active forms attracted considerable interest.MethodA reaction coordinate is computed for the transition between the active to inactive conformation in Abl kinase with a focus on the DFG-in to DFG-out flip. The method of Rock Climbing is used to construct a path locally, which is subsequently optimized using a functional of the entire path. The discrete coordinate sets along the reaction path are used in a Milestoning calculation of the free energy landscape and the rate of the transition.ResultsThe estimated transition times are between a few milliseconds and seconds, consistent with simulations of the kinetics and with indirect experimental data. The activation requires the transient dissociation of the salt bridge between Lys271 and Glu286. The salt bridge reforms once the DFG motif is stabilized by a locked conformation of Phe382. About ten residues are identified that contribute significantly to the process and are included as part of the reaction space.ConclusionsThe transition from DFG-in to DFG-out in Abl kinase was simulated using atomic resolution of a fully solvated protein yielding detailed description of the kinetics and the mechanism of the DFG flip. The results are consistent with other computational methods that simulate the kinetics and with some indirect experimental measurements.General significanceThe activation of kinases includes a conformational transition of the DFG motif that is important for enzyme activity but is not accessible to conventional Molecular Dynamics. We propose a detailed mechanism for the transition, at a timescale longer than conventional MD, using a combination of reaction path and Milestoning algorithms. The mechanism includes local structural adjustments near the binding site as well as collective interactions with more remote residues.

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

Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.

Publications

Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.

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