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Title: Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment
Authors: Marzinek, J.K 
Lakshminarayanan, R 
Goh, E
Huber, R.G
Panzade, S
Verma, C 
Bond, P.J 
Keywords: peptide
virus fusion protein
circular dichroism
molecular dynamics
molecular model
protein conformation
protein folding
Circular Dichroism
Models, Molecular
Molecular Dynamics Simulation
Protein Conformation
Protein Folding
Spectrometry, Fluorescence
Viral Fusion Proteins
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Marzinek, J.K, Lakshminarayanan, R, Goh, E, Huber, R.G, Panzade, S, Verma, C, Bond, P.J (2016). Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment. Scientific Reports 6 : 19160. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Conformational changes in the envelope proteins of flaviviruses help to expose the highly conserved fusion peptide (FP), a region which is critical to membrane fusion and host cell infection, and which represents a significant target for antiviral drugs and antibodies. In principle, extended timescale atomic-resolution simulations may be used to characterize the dynamics of such peptides. However, the resultant accuracy is critically dependent upon both the underlying force field and sufficient conformational sampling. In the present study, we report a comprehensive comparison of three simulation methods and four force fields comprising a total of more than 40 1/4s of sampling. Additionally, we describe the conformational landscape of the FP fold across all flavivirus family members. All investigated methods sampled conformations close to available X-ray structures, but exhibited differently populated ensembles. The best force field / sampling combination was sufficiently accurate to predict that the solvated peptide fold is less ordered than in the crystallographic state, which was subsequently confirmed via circular dichroism and spectrofluorometric measurements. Finally, the conformational landscape of a mutant incapable of membrane fusion was significantly shallower than wild-type variants, suggesting that dynamics should be considered when therapeutically targeting FP epitopes.
Source Title: Scientific Reports
ISSN: 2045-2322
DOI: 10.1038/srep19160
Rights: Attribution 4.0 International
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