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Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment

Henriques, Joao LU ; Cragnell, Carolina LU and Skepö, Marie LU (2015) In Journal of Chemical Theory and Computation 11(7). p.3420-3431
Abstract
An increasing number of studies using molecular dynamics (MD) simulations of unfolded and intrinsically disordered proteins (IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art MD force fields, of the AMBER and GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and Size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational Class analysis. Our results show... (More)
An increasing number of studies using molecular dynamics (MD) simulations of unfolded and intrinsically disordered proteins (IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art MD force fields, of the AMBER and GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and Size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational Class analysis. Our results show that, indeed, standard force fields sample conformations that are too compact, being systematically unable to reproduce experimental evidence such as the scattering function, the shape of the protein as compared with the Kratky plot, and intrapeptide distances obtained through the pair distance distribution function, p(r). The consistency of this deviation suggests that the problem is not mainly due to protein-protein or water-water interactions, whose parametrization varies the most between force fields and water models. In fact, as originally proposed in [Best et al. J. Chem. Theory Comput. 2014, 10, 5113-5124.], balanced protein-water interactions may be the key to solving this problem. Our simulations using this approach produce results in very good agreement with experiment. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
11
issue
7
pages
3420 - 3431
publisher
The American Chemical Society
external identifiers
  • wos:000358104800051
  • pmid:26575776
  • scopus:84939645682
ISSN
1549-9618
DOI
10.1021/ct501178z
language
English
LU publication?
yes
id
bcea08cf-3ac4-4ce3-9c38-eb6d0e55187d (old id 7779499)
date added to LUP
2015-09-18 11:40:20
date last changed
2017-11-05 03:19:40
@article{bcea08cf-3ac4-4ce3-9c38-eb6d0e55187d,
  abstract     = {An increasing number of studies using molecular dynamics (MD) simulations of unfolded and intrinsically disordered proteins (IDPs) suggest that current force fields sample conformations that are overly collapsed. Here, we study the applicability of several state-of-the-art MD force fields, of the AMBER and GROMOS variety, for the simulation of Histatin 5, a short (24 residues) cationic salivary IDP with antimicrobial and antifungal properties. The quality of the simulations is assessed in three complementary analyses: (i) protein shape and Size comparison with recent experimental small-angle X-ray scattering data; (ii) secondary structure prediction; (iii) energy landscape exploration and conformational Class analysis. Our results show that, indeed, standard force fields sample conformations that are too compact, being systematically unable to reproduce experimental evidence such as the scattering function, the shape of the protein as compared with the Kratky plot, and intrapeptide distances obtained through the pair distance distribution function, p(r). The consistency of this deviation suggests that the problem is not mainly due to protein-protein or water-water interactions, whose parametrization varies the most between force fields and water models. In fact, as originally proposed in [Best et al. J. Chem. Theory Comput. 2014, 10, 5113-5124.], balanced protein-water interactions may be the key to solving this problem. Our simulations using this approach produce results in very good agreement with experiment.},
  author       = {Henriques, Joao and Cragnell, Carolina and Skepö, Marie},
  issn         = {1549-9618},
  language     = {eng},
  number       = {7},
  pages        = {3420--3431},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment},
  url          = {http://dx.doi.org/10.1021/ct501178z},
  volume       = {11},
  year         = {2015},
}