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Title: Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model

Abstract

Determination of protein-protein binding affinity values is key to understanding various underlying biological phenomena, such as how missense variations change protein-protein binding. Most existing nonrigorous (fast) and rigorous (slow) methods that rely on all-atom representation of the proteins force the user to choose between speed and accuracy. In an attempt to achieve balance between speed and accuracy, we have combined rigorous umbrella sampling molecular dynamics simulation with a coarse-grained protein model. We predicted the effect of missense variations on binding affinity by selecting three protein-protein systems and comparing results to empirical relative binding affinity values and to nonrigorous modeling approaches. We obtained significant improvement both in our ability to discern stabilizing from destabilizing missense variations and in the correlation between predicted and experimental values compared to nonrigorous approaches. Overall our results suggest that using a rigorous affinity calculation method with coarse-grained protein models could offer fast and reliable predictions of protein-protein binding free energies.

Authors:
ORCiD logo [1];  [2]
  1. Center for Modeling Complex Interactions, University of Idaho, Moscow, Idaho 83844, United States
  2. Department of Physics, University of Idaho, Moscow, Idaho 83844, United States
Publication Date:
Research Org.:
Univ. of Idaho, Moscow, ID (United States)
Sponsoring Org.:
USDOE Office of Nuclear Energy (NE)
OSTI Identifier:
1417063
Alternate Identifier(s):
OSTI ID: 1508328
Grant/Contract Number:  
AC07-05ID14517
Resource Type:
Published Article
Journal Name:
Journal of Chemical Theory and Computation
Additional Journal Information:
Journal Name: Journal of Chemical Theory and Computation Journal Volume: 14 Journal Issue: 2; Journal ID: ISSN 1549-9618
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Patel, Jagdish Suresh, and Ytreberg, F. Marty. Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model. United States: N. p., 2018. Web. doi:10.1021/acs.jctc.7b00660.
Patel, Jagdish Suresh, & Ytreberg, F. Marty. Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model. United States. doi:10.1021/acs.jctc.7b00660.
Patel, Jagdish Suresh, and Ytreberg, F. Marty. Tue . "Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model". United States. doi:10.1021/acs.jctc.7b00660.
@article{osti_1417063,
title = {Fast Calculation of Protein–Protein Binding Free Energies Using Umbrella Sampling with a Coarse-Grained Model},
author = {Patel, Jagdish Suresh and Ytreberg, F. Marty},
abstractNote = {Determination of protein-protein binding affinity values is key to understanding various underlying biological phenomena, such as how missense variations change protein-protein binding. Most existing nonrigorous (fast) and rigorous (slow) methods that rely on all-atom representation of the proteins force the user to choose between speed and accuracy. In an attempt to achieve balance between speed and accuracy, we have combined rigorous umbrella sampling molecular dynamics simulation with a coarse-grained protein model. We predicted the effect of missense variations on binding affinity by selecting three protein-protein systems and comparing results to empirical relative binding affinity values and to nonrigorous modeling approaches. We obtained significant improvement both in our ability to discern stabilizing from destabilizing missense variations and in the correlation between predicted and experimental values compared to nonrigorous approaches. Overall our results suggest that using a rigorous affinity calculation method with coarse-grained protein models could offer fast and reliable predictions of protein-protein binding free energies.},
doi = {10.1021/acs.jctc.7b00660},
journal = {Journal of Chemical Theory and Computation},
number = 2,
volume = 14,
place = {United States},
year = {2018},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1021/acs.jctc.7b00660

Citation Metrics:
Cited by: 3 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: Three-dimensional structures of test protein−protein complexes. System names (PDB IDs) are given above each panel (1PPF, 1BRS, and 3HFM). Each protein pair is colored in orange and green. The red spheres along the interface of the protein complex indicate the sites of the single missense variations chosen formore » the present study.« less

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Works referencing / citing this record:

From quantum to subcellular scales: multi-scale simulation approaches and the SIRAH force field
journal, April 2019

  • Machado, Matías R.; Zeida, Ari; Darré, Leonardo
  • Interface Focus, Vol. 9, Issue 3
  • DOI: 10.1098/rsfs.2018.0085

From quantum to subcellular scales: multi-scale simulation approaches and the SIRAH force field
journal, April 2019

  • Machado, Matías R.; Zeida, Ari; Darré, Leonardo
  • Interface Focus, Vol. 9, Issue 3
  • DOI: 10.1098/rsfs.2018.0085

    Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.