Journal article
Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields
The journal of physical chemistry. B, v 125(25), pp 6897-6911
01 Jul 2021
PMID: 34143637
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Protein self-assembly plays an important role in cellular processes. Whereas molecular dynamics (MD) represents a powerful tool in studying assembly mechanisms, its predictions depend on the accuracy of underlying force fields, which are known to overly promote protein assembly. We here examine villin headpiece domain, HP36, which remains soluble at concentrations amenable to MD studies. The experimental characterization of soluble HP36 at concentrations of 0.05 to 1 mM reveals concentration-independent 90% monomeric and 10% dimeric populations. Extensive all-atom MD simulations at two protein concentrations, 0.9 and 8.5 mM, probe the HP36 dimer population, stability, and kinetics of dimer formation within two MD force fields, Amber ff14SB and CHARMM36m. MD results demonstrate that whereas CHARMM36m captures experimental HP36 monomer populations at the lower concentration, both force fields overly promote HP36 association at the higher concentration. Moreover, contacts stabilizing HP36 dimers are force-field-dependent. CHARMM36m produces consistently higher HP36 monomer populations, lower association rates, and weaker dependence of these quantities on the protein concentration than Amber ff14SB. Nonetheless, the highest monomer populations and dissociation constants are observed when the TIP3P water model in Amber ff14SB is replaced by TIP4P/2005, showcasing the critical role of the water model in addressing the protein solubility problem in MD.
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Details
- Title
- Soluble State of Villin Headpiece Protein as a Tool in the Assessment of MD Force Fields
- Creators
- Brian Andrews - Drexel UniversityKaho Long - Drexel UniversityBrigita Urbanc - Drexel University
- Publication Details
- The journal of physical chemistry. B, v 125(25), pp 6897-6911
- Publisher
- American Chemical Society; Washington, DC
- Number of pages
- 15
- Grant note
- MCB-1817650; OAC-1919691 / National Science Foundation; National Science Foundation (NSF)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000670636400016
- Scopus ID
- 2-s2.0-85110113729
- Other Identifier
- 991019168342304721
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- Web of Science research areas
- Chemistry, Physical