Efficient Atomistic Simulation of Pathways and Calculation of Rate Constants for a Protein-Peptide Binding Process: Application to the MDM2 Protein and an Intrinsically Disordered p53 Peptide

Matthew C. Zwier, Adam J. Pratt, Joshua L. Adelman, Joseph W. Kaus, Daniel Zuckerman, Lillian T. Chong

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The characterization of protein binding processes - with all of the key conformational changes - has been a grand challenge in the field of biophysics. Here, we have used the weighted ensemble path sampling strategy to orchestrate molecular dynamics simulations, yielding atomistic views of protein-peptide binding pathways involving the MDM2 oncoprotein and an intrinsically disordered p53 peptide. A total of 182 independent, continuous binding pathways were generated, yielding a kon that is in good agreement with experiment. These pathways were generated in 15 days using 3500 cores of a supercomputer, substantially faster than would be possible with "brute force" simulations. Many of these pathways involve the anchoring of p53 residue F19 into the MDM2 binding cleft when forming the metastable encounter complex, indicating that F19 may be a kinetically important residue. Our study demonstrates that it is now practical to generate pathways and calculate rate constants for protein binding processes using atomistic simulation on typical computing resources.

Original languageEnglish (US)
Pages (from-to)3440-3445
Number of pages6
JournalJournal of Physical Chemistry Letters
Volume7
Issue number17
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Intrinsically Disordered Proteins
Peptides
peptides
Rate constants
Biophysics
proteins
Proteins
Supercomputers
Oncogene Proteins
Molecular dynamics
simulation
Sampling
Computer simulation
biophysics
supercomputers
encounters
Experiments
resources
sampling
Protein Binding

ASJC Scopus subject areas

  • Materials Science(all)

Cite this

Efficient Atomistic Simulation of Pathways and Calculation of Rate Constants for a Protein-Peptide Binding Process : Application to the MDM2 Protein and an Intrinsically Disordered p53 Peptide. / Zwier, Matthew C.; Pratt, Adam J.; Adelman, Joshua L.; Kaus, Joseph W.; Zuckerman, Daniel; Chong, Lillian T.

In: Journal of Physical Chemistry Letters, Vol. 7, No. 17, 01.09.2016, p. 3440-3445.

Research output: Contribution to journalArticle

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