10.6084/M9.FIGSHARE.5918491
Jiajie Xiao
Melvin, Ryan L.
Ryan L.
Melvin
Salsbury, Freddie R.
Freddie R.
Salsbury
Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning
Taylor & Francis
2018
Journal contribution
Biophysics
Biochemistry
Cell Biology
Genetics
FOS: Biological sciences
FOS: Biological sciences
Physiology
39999 Chemical Sciences not elsewhere classified
FOS: Chemical sciences
FOS: Chemical sciences
69999 Biological Sciences not elsewhere classified
Cancer
Hematology
Computational Biology
2018-02-23
2019-02-26
2018
10.1080/07391102.2018.1445032
4096595 Bytes
Creative Commons Attribution 4.0 International
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<sup>+</sup> 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 features in the wild-type and ΔK9 mutant forms of thrombin, we predict that seven pairs of critical hydrogen bonding interactions are significant for establishing distinct behaviors of wild-type thrombin and its ΔK9 mutant form. Our calculations indicate the LYS9 in the light chain has both localized and long-range allosteric effects on thrombin, supporting the opinion that light chain has an important role as an allosteric effector.