Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning

Journal of Biomolecular Structure & Dynamics
Jiajie XiaoFreddie R Salsbury

Abstract

Thrombin is a key component for chemotherapeutic and antithrombotic therapy development. As the physiologic and pathologic roles of the light chain still remain vague, here, we continue previous efforts to understand the impacts of the disease-associated single deletion of LYS9 in the light chain. By combining supervised and unsupervised machine learning methodologies and more traditional structural analyses on data from 10 μs molecular dynamics simulations, we show that the conformational ensemble of the ΔK9 mutant is significantly perturbed. Our analyses consistently indicate that LYS9 deletion destabilizes both the catalytic cleft and regulatory functional regions and result in some conformational changes that occur in tens to hundreds of nanosecond scaled motions. We also reveal that the two forms of thrombin each prefer a distinct binding mode of a Na+ ion. We expand our understanding of previous experimental observations and shed light on the mechanisms of the LYS9 deletion associated bleeding disorder by providing consistent but more quantitative and detailed structural analyses than early studies in literature. With a novel application of supervised learning, i.e. the decision tree learning on the hydrogen bonding featu...Continue Reading

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Citations

Sep 3, 2020·Journal of Biomolecular Structure & Dynamics·Zhipeng TangFei Liu
Nov 20, 2019·International Journal of Biological Macromolecules·Fangyuan Chen, Guangrong Huang
Jan 16, 2021·Journal of Chemical Information and Modeling·Dizhou WuFreddie R Salsbury

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Methods Mentioned

BETA
NMR
PCA

Software Mentioned

ACEMD
MDTraj
Matlab
PyEmma
Metrocubo
Modeller
VMD
Tachyon
psfgen
SASA

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