Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures

Stephen D LuCore; Jacob M Litman; Kyle T Powers; Shibo Gao; Ava M Lynn; William T A Tollefson; Timothy D Fenn; M Todd Washington; Michael J Schnieders

doi:10.1016/j.bpj.2015.06.062

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Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures

Journal article

Open access

Peer reviewed

Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures

Stephen D LuCore, Jacob M Litman, Kyle T Powers, Shibo Gao, Ava M Lynn, William T A Tollefson, Timothy D Fenn, M Todd Washington and Michael J Schnieders

Biophysical journal, Vol.109(4), pp.816-826

08/18/2015

DOI: 10.1016/j.bpj.2015.06.062

PMCID: PMC4547145

PMID: 26287633

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https://doi.org/10.1016/j.bpj.2015.06.062View

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Abstract

A balance of van der Waals, electrostatic, and hydrophobic forces drive the folding and packing of protein side chains. Although such interactions between residues are often approximated as being pairwise additive, in reality, higher-order many-body contributions that depend on environment drive hydrophobic collapse and cooperative electrostatics. Beginning from dead-end elimination, we derive the first algorithm, to our knowledge, capable of deterministic global repacking of side chains compatible with many-body energy functions. The approach is applied to seven PCNA x-ray crystallographic data sets with resolutions 2.5-3.8 Å (mean 3.0 Å) using an open-source software. While PDB_REDO models average an Rfree value of 29.5% and MOLPROBITY score of 2.71 Å (77th percentile), dead-end elimination with the polarizable AMOEBA force field lowered Rfree by 2.8-26.7% and improved mean MOLPROBITY score to atomic resolution at 1.25 Å (100th percentile). For structural biology applications that depend on side-chain repacking, including x-ray refinement, homology modeling, and protein design, the accuracy limitations of pairwise additivity can now be eliminated via polarizable or quantum mechanical potentials.

Protein Folding

Algorithms

Software

Mutation

Datasets as Topic

Models, Chemical

Protein Structure, Secondary

Access to Information

Crystallography, X-Ray

Static Electricity

Proliferating Cell Nuclear Antigen - chemistry

Quantum Theory

Proliferating Cell Nuclear Antigen - genetics

Hydrophobic and Hydrophilic Interactions

Details

Title: Subtitle: Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures
Creators: Stephen D LuCore - Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa
Jacob M Litman - Department of Biochemistry, University of Iowa, Iowa City, Iowa
Kyle T Powers - Department of Biochemistry, University of Iowa, Iowa City, Iowa
Shibo Gao - Department of Biochemistry, University of Iowa, Iowa City, Iowa
Ava M Lynn - Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa
William T A Tollefson - Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa
Timothy D Fenn - Boehringer Ingelheim, Ridgefield, Connecticut
M Todd Washington - Department of Biochemistry, University of Iowa, Iowa City, Iowa
Michael J Schnieders - Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa; Department of Biochemistry, University of Iowa, Iowa City, Iowa. Electronic address: michael-schnieders@uiowa.edu
Resource Type: Journal article
Publication Details: Biophysical journal, Vol.109(4), pp.816-826
Publisher: United States
DOI: 10.1016/j.bpj.2015.06.062
PMID: 26287633
PMCID: PMC4547145
ISSN: 0006-3495
eISSN: 1542-0086
Grant note: GM081433 / NIGMS NIH HHS T32 GM067795 / NIGMS NIH HHS T32-GM008365 / NIGMS NIH HHS T32-GM067795 / NIGMS NIH HHS R01 DC002842 / NIDCD NIH HHS T32 GM008365 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 08/18/2015
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiation Oncology; Biochemistry and Molecular Biology
Record Identifier: 9984024523202771

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