Molecular Dynamics Simulations of Intrinsically Disordered Proteins: Force Field Evaluation and Comparison with Experiment
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/7779499
- author
- Henriques, Joao LU ; Cragnell, Carolina LU and Skepö, Marie LU
- organization
- publishing date
- 2015
- 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 (ACS)
- external identifiers
-
- wos:000358104800051
- pmid:26575776
- scopus:84939645682
- pmid:26575776
- ISSN
- 1549-9618
- DOI
- 10.1021/ct501178z
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
- id
- bcea08cf-3ac4-4ce3-9c38-eb6d0e55187d (old id 7779499)
- date added to LUP
- 2016-04-01 10:50:23
- date last changed
- 2023-01-02 08:14:16
@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 (ACS)}},
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}},
doi = {{10.1021/ct501178z}},
volume = {{11}},
year = {{2015}},
}