title: Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study.
abstract: The pathogenic dengue virus (DV) is a growing global threat, particularly in South East Asia, for which there is no specific treatment available. The virus possesses a two-component (NS2B/NS3) serine protease that cleaves the viral precursor proteins. Here, we performed molecular dynamics simulations of the NS2B/NS3 protease complexes with six peptide substrates (capsid, intNS3, 2A/2B, 4B/5, 3/4A and 2B/3 containing the proteolytic site between P(1) and P(1)' subsites) of DV type 2 to compare the specificity of the protein-substrate binding recognition. Although all substrates were in the active conformation for cleavage reaction by NS2B/NS3 protease, their binding strength was somewhat different. The simulated results of intermolecular hydrogen bonds and decomposition energies suggested that among the ten substrate residues (P(5)-P(5)') the P(1) and P(2) subsites play a major role in the binding with the focused protease. The arginine residue at these two subsites was found to be specific preferential binding at the active site with a stabilization energy of <-10 kcal mol(-1). Besides, the P(3), P(1)', P(2)' and P(4)' subsites showed a less contribution in binding interaction (<-2 kcal mol(-1)). The catalytic water was detected nearby the carbonyl oxygen of the P(1) reacting center of the capsid, intNS3, 2A/2B and 4B/5 peptides. These results led to the order of absolute binding free energy (ΔGbind) between these substrates and the NS2B/NS3 protease ranked as capsid>intNS3>2A/2B>4B/5>3/4A>2B/3 in a relative correspondence with previous experimentally derived values.
authors.affiliation: Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand; Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Yotmanee
authors.affiliation: Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand; Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
authors.forename: Kanin
authors.initials: K
authors.lastname: Wichapong
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia; Natural Product and Drug Discovery Centre, Malaysian Institutes of Pharmaceuticals and Nutraceuticals, National Institutes of Biotechnology Malaysia, Ministry of Science, Technology and Innovation, Block 5-A, Halaman Bukit Gambir, 11700, Penang, Malaysia.
authors.forename: Sy Bing
authors.initials: SB
authors.lastname: Choi
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Pulau Pinang, Malaysia; Natural Product and Drug Discovery Centre, Malaysian Institutes of Pharmaceuticals and Nutraceuticals, National Institutes of Biotechnology Malaysia, Ministry of Science, Technology and Innovation, Block 5-A, Halaman Bukit Gambir, 11700, Penang, Malaysia. Electronic address: habibahw@usm.my.
authors.forename: Habibah A
authors.initials: HA
authors.lastname: Wahab
authors.affiliation: Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
authors.forename: Nawee
authors.initials: N
authors.lastname: Kungwan
authors.affiliation: Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand. Electronic address: supot.h@chula.ac.th.
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D036022:Capsid Proteins / Q000378:metabolism; D002384:Catalysis; D020134:Catalytic Domain; D003716:Dengue Virus / Q000201:enzymology*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D013816:Thermodynamics; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000378:metabolism*; D000085242:Viral Proteases
chemical_list: D036022:Capsid Proteins; D010455:Peptides; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C080102:NS2B protein, flavivirus; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases
keywords: Dengue virus; Molecular dynamics; NS2B/NS3 protease; Pathogenic; Polypeptide