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Title: Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study
Authors: Pathumwadee Yotmanee
Thanyada Rungrotmongkol
Kanin Wichapong
Sy Bing Choi
Habibah A. Wahab
Nawee Kungwan
Supot Hannongbua
Keywords: Chemistry
Computer Science
Materials Science
Issue Date: 17-Jun-2015
Abstract: © 2015 Elsevier Inc. All rights reserved. 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<sup>1</sup> and P<sup>1</sup>′ 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<sup>5</sup>-P<sup>5</sup>′) the P<sup>1</sup> and P<sup>2</sup> 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<sup>-1</sup>. Besides, the P<sup>3</sup>, P<sup>1</sup>′, P<sup>2</sup>′ and P<sup>4</sup>′ subsites showed a less contribution in binding interaction (<-2 kcal mol<sup>-1</sup>). The catalytic water was detected nearby the carbonyl oxygen of the P<sup>1</sup> reacting center of the capsid, intNS3, 2A/2B and 4B/5 peptides. These results led to the order of absolute binding free energy (ΔG<inf>bind</inf>) 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.
ISSN: 18734243
Appears in Collections:CMUL: Journal Articles

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