title: Characterizing the Conformational Landscape of Flavivirus Fusion Peptides via Simulation and Experiment.
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 μs 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.
authors.affiliation: National University of Singapore, Department of Biological Sciences, 14 Science Drive 4, Singapore 117543.|Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Marzinek
authors.affiliation: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 12, Singapore 169856.
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.affiliation: Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower Level 12, Singapore 169856.
authors.forename: Eunice
authors.initials: E
authors.lastname: Goh
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.
authors.forename: Roland G
authors.initials: RG
authors.lastname: Huber
authors.affiliation: Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.
authors.forename: Sadhana
authors.initials: S
authors.lastname: Panzade
authors.affiliation: National University of Singapore, Department of Biological Sciences, 14 Science Drive 4, Singapore 117543.|Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.affiliation: National University of Singapore, Department of Biological Sciences, 14 Science Drive 4, Singapore 117543.|Bioinformatics Institute (A*STAR), 30 Biopolis Str., #07-01 Matrix, Singapore 138671.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
mesh_terms: D002942:Circular Dichroism; D005416:Flavivirus; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D013050:Spectrometry, Fluorescence; D014760:Viral Fusion Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D010455:Peptides; D014760:Viral Fusion Proteins