Conformational Dynamics of Two Natively Unfolded Fragment Peptides: Comparison of the AMBER and CHARMM Force Fields.

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TitleConformational Dynamics of Two Natively Unfolded Fragment Peptides: Comparison of the AMBER and CHARMM Force Fields.
Publication TypeJournal Article
Year of Publication2015
AuthorsChen, W, Shi, C, Mackerell, AD, Shen, J
JournalJ Phys Chem B
Volume119
Issue25
Pagination7902-10
Date Published2015 Jun 25
ISSN1520-5207
KeywordsHydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Molecular Dynamics Simulation, Nuclear Magnetic Resonance, Biomolecular, Protein Conformation, Protein Unfolding
Abstract

Physics-based force fields are the backbone of molecular dynamics simulations. In recent years, significant progress has been made in the assessment and improvement of commonly used force fields for describing conformational dynamics of folded proteins. However, the accuracy for the unfolded states remains unclear. The latter is however important for detailed studies of protein folding pathways, conformational transitions involving unfolded states, and dynamics of intrinsically disordered proteins. In this work, we compare the three commonly used force fields, AMBER ff99SB-ILDN, CHARMM22/CMAP, and CHARMM36, for modeling the natively unfolded fragment peptides, NTL9(1-22) and NTL9(6-17), using explicit-solvent replica-exchange molecular dynamics simulations. All three simulations show that NTL9(6-17) is completely unstructured, while NTL9(1-22) transiently samples various β-hairpin states, reminiscent of the first β-hairpin in the structure of the intact NTL9 protein. The radius of gyration of the two peptides is force field independent but likely underestimated due to the current deficiency of additive force fields. Compared to the CHARMM force fields, ff99SB-ILDN gives slightly higher β-sheet propensity and more native-like residual structures for NTL9(1-22), which may be attributed to its known β preference. Surprisingly, only two sequence-local pairs of charged residues make appreciable ionic contacts in the simulations of NTL9(1-22), which are sampled slightly more by the CHARMM force fields. Taken together, these data suggest that the current CHARMM and AMBER force fields are globally in agreement in modeling the unfolded states corresponding to β-sheet in the folded structure, while differing in details such as the native-likeness of the residual structures and interactions.

DOI10.1021/acs.jpcb.5b02290
Alternate JournalJ Phys Chem B
PubMed ID26020564
PubMed Central IDPMC4685472
Grant ListR01 GM072558 / GM / NIGMS NIH HHS / United States
GM051501 / GM / NIGMS NIH HHS / United States
R01 GM098818 / GM / NIGMS NIH HHS / United States
R01 GM051501 / GM / NIGMS NIH HHS / United States
R29 GM051501 / GM / NIGMS NIH HHS / United States
GM098818 / GM / NIGMS NIH HHS / United States
GM072558 / GM / NIGMS NIH HHS / United States