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PreprintCited by 68Protein Structure and DynamicsProtein Kinase Regulation and GTPase SignalingComputational Drug Discovery Methods

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Towards simple kinetic models of functional dynamics for a kinase subfamily

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Sultan, Mohammad M., Kiss, Gert, Pande, Vijay·2017·Nature Chemistry
DOI 10.1101/228528

Preprint — published as 10.1038/s41557-018-0077-9 · Paper page

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Abstract

Kinases are ubiquitous enzymes involved in the regulation of critical cellular pathways and have been implicated in several cancers. Consequently, the kinetics and thermodynamics of prototypical kinases are of interest and have been the subject of numerous experimental studies. In-silico modeling of the conformational ensembles of these enzymes, on the other hand, is lacking due to inherent computational limitations. Recent algorithmic advances combined with homology modeling and parallel simulations allow us to address this computational sampling bottleneck. Here, we present the results of molecular dynamics (MD) studies for seven Src family kinase (SFK) members Fyn, Lyn, Lck, Hck, Fgr, Yes, and Blk. We present a sequence invariant extension to Markov state models (MSMs), which allows us to quantitatively compare the structural ensembles of the seven kinases. Our findings indicate that in the absence of their regulatory partners, SFK members have similar in-silico dynamics with active state populations ranging from 4-40% and activation timescales in the hundreds of microseconds. Furthermore, we observe several potentially druggable intermediate states, including a pocket next to the ATP binding site that could be potentially targeted via a small molecule inhibitors. These results establish the utility of MSMs for studying protein families.

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Metadata

Authors
Sultan, M. M., Kiss, G., & Pande, V.
Affiliations
  • Stanford University (US)
  • Revolution Medicines (United States) (US)
Corresponding author
Pande, Vijay
ORCID
Venue
Nature Chemistry
Publisher
openRxiv
Published
2017-12-03
Volume
10
Issue
9
Pages
903-909
ISSN
1755-4330 (ISSN-L)
DOI
10.1101/228528
OpenAlex
W2950292741
Cited by
68
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 9 · 2018: 3
FWCI
3.02
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Chemistry (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation (0954714)
  • National Institutes of Health (1s10rr026647-01)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
Keywords
Src family kinases, kinase activation, conformational dynamics, Markov state models, ATP binding site, small-molecule kinase inhibitors, Fyn, Lyn kinase, Lck, Hck, Fgr, Yes, BLK, enzyme kinetics
MeSH terms
Adenosine Triphosphate, Binding Sites, Kinetics, Markov Chains, Models, Biological, Protein Structure, Tertiary, src-Family Kinases, Amino Acid Motifs, Protein Kinase Inhibitors, Small Molecule Libraries, Molecular Dynamics Simulation

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