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Title: Coarse-Grained Molecular Modeling of the Solution Structure Ensemble of Dengue Virus Nonstructural Protein 5 with Small-Angle X-ray Scattering Intensity
Authors: Zhu, Guanhua
Saw, Wuan Geok
Nalaparaju, Anjaiah
Grüber, Gerhard
Lu, Lanyuan
Keywords: Dengue Virus
Small-Angle X-ray Scattering Intensity
Issue Date: 2017
Source: Zhu, G., Saw, W. G., Nalaparaju, A., Grüber, G., & Lu, L. (2017). Coarse-Grained Molecular Modeling of the Solution Structure Ensemble of Dengue Virus Nonstructural Protein 5 with Small-Angle X-ray Scattering Intensity. The Journal of Physical Chemistry B, 121(10), 2252-2264.
Series/Report no.: The Journal of Physical Chemistry B
Abstract: An ensemble-modeling scheme incorporating coarse-grained simulations with experimental small-angle X-ray scattering (SAXS) data is applied to dengue virus 2 (DENV2) nonstructural protein 5 (NS5). NS5 serves a key role in viral replication through its two domains that are connected by a 10-residue polypeptide segment. A set of representative structures is generated from a simulated structure pool using SAXS data fitting by the non-negativity least squares (NNLS) or standard ensemble optimization method (EOM) based on a genetic algorithm (GA). It is found that a proper low-energy threshold of the structure pool is necessary to produce a conformational ensemble of two representative structures by both NNLS and GA that agrees well with the experimental SAXS profile. The stability of the constructed ensemble is validated also by molecular dynamics simulations with an all-atom force field. The constructed ensemble successfully revealed the domain–domain orientation and domain-contacting interface of DENV2 NS5. Using experimental data fitting and additional investigations with synthesized data, it is found that energy restraint on the conformational pool is necessary to avoid overinterpretation of experimental data by spurious conformational representations.
ISSN: 1520-6106
DOI: 10.1021/acs.jpcb.7b00051
Rights: © 2017 American Chemical Society. This is the author created version of a work that has been peer reviewed and accepted for publication by The Journal of Physical Chemistry B, American Chemical Society. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [].
Fulltext Permission: open
Fulltext Availability: With Fulltext
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