Mutation-mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica Gaussian
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Mutation‑mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica Gaussian accelerated molecular dynamics Jianzhong Chen1 · Wei Wang1 · Haibo Sun1 · Laixue Pang1 · Baohua Yin2 Received: 14 August 2020 / Accepted: 14 October 2020 © Springer Nature Switzerland AG 2020
Abstract Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In the current work, multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations, molecular mechanics generalized Born surface area (MM-GBSA) and free energy landscapes were coupled to explore influences of mutations L1198F, L1198F/C1156Y, and C1156Y on the binding of the first ALK inhibitor crizotinib to ALK. The results suggest that three mutations obviously affect structural flexibility, motion modes and conformational changes of ALKs. L1198F and L1198F/C1156Y strengthen the binding of crizotinib to the mutated ALKs but C1156Y induces evident drug resistance toward crizotinib. Analyses of free energy landscapes show that stability in the orientation and positions of crizotinib relative to ALK plays a vital role in alleviating drug resistance of mutations toward crizotinib. Residue-based free energy decomposition method was utilized to evaluate the contributions of separate residues to the binding of crizotinib. The results not only indicate that the tuning of point mutation L1198F on interaction networks of crizotinib with ALK can be regarded as a possible strategy to relieve drug resistance of the mutated ALK but also further verify that residues L1122, V1130, L1196, L1198, M1199, and L1256 can be used as efficient targets of anti-drug resistance design induced by mutations. Keywords anaplastic lymphoma kinase · MR-GaMD simulations · Free energy landscapes · Drug resistance · MM-GBSA · Principal component analysis
Introduction Anaplastic lymphoma kinase (ALK), a receptor kinase, is a member of insulin receptor superfamily of tyrosine kinase. Expression of ALK in normal human tissues is only detected Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00355-5) contains supplementary material, which is available to authorized users. * Jianzhong Chen [email protected]; [email protected] * Baohua Yin [email protected] 1
School of Science, Shandong Jiaotong University, Jinan 250357, China
School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
2
in adult brain tissue, which plays a significant role in development of brain and also exerts an important influence on specific neurons in human nervous system [1]. Mice with the ALK knockout have normal growth and live a full life span without obvious abnormalities but show an anti-depressive profile with enhan
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