Abstract
Classical force fields are essential for computer simulations of proteins and are typically parameterized to reproduce secondary and tertiary structure of isolated proteins. However, while protein-protein interactions are ubiquitous in nature, they are not considered in parameterization efforts and are far less understood than isolated proteins. A better characterization of intermolecular interactions is widely recognized as a key to revolutionizing drug and therapeutic developments with high-throughput computational screening. Urgently needed is a critical assessment of the performance of modern protein force fields against first-principles electronic structure methods and experiments. In a daring step toward this goal, we here describe a comparison of peptide folding dynamics as predicted by a molecular mechanics force field on the one hand and by an approximate electronic structure quantum mechanical (QM) method based on density-functional tight-binding (DFTB) on the other. We further compare the dynamics from straightforward DFTB simulations with a near-linear scaling version of DFTB for massively parallel computation based on the fragment molecular orbital (FMO-DFTB) method. We illustrate differences between the phenomenology of the folding dynamics from these three methods for a small model peptide, as well as charge polarization and dynamic fluctuations, point out possible correlations and implications for force field developers, and discuss the lessons learned that might become applicable to future predictive high-throughput computer screening for personalized neoantigen cancer therapy.
Original language | English |
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Title of host publication | Methods in Molecular Biology |
Publisher | Humana Press Inc. |
Pages | 149-161 |
Number of pages | 13 |
DOIs | |
State | Published - 2020 |
Publication series
Name | Methods in Molecular Biology |
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Volume | 2114 |
ISSN (Print) | 1064-3745 |
ISSN (Electronic) | 1940-6029 |
Funding
S.I. acknowledges support by the Laboratory Directed Research and Development (LDRD) Program of Oak Ridge National Laboratory (ORNL). ORNL is managed by UT-Battelle LLC, for DOE under Contract No. DE-AC05-00OR22725. M.H.E. acknowledges support from the DOE Science Undergraduate Laboratory Internship (SULI) program. V.Q.V. acknowledges support from an Energy Science and Engineering Fellowship of the Bredesen Center for Interdisciplinary Research and Graduate Education at the University of Tennessee, Knoxville. M.T. acknowledges support from ORNL’s summer research appointment program for faculty of Historically Black Colleges and Universities (HBCUs) and other Minority Educational Institutions (MEIs). Calculations were performed at the High Performance Computer Center of Tennessee Technological University and at the Center for Nanophase Materials Sciences, which is a US Department of Energy Office of Science User Facility.
Keywords
- Density-functional tight-binding
- Molecular dynamics simulations
- Near-linear scaling methods
- Neoantigen therapy