Binding specificity of polypeptide substrates in NS2B/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study

• Main Authors: Pathumwadee Yotmanee, Thanyada Rungrotmongkol, Kanin Wichapong, Sy Bing Choi, Habibah A. Wahab, Nawee Kungwan, Supot Hannongbua
• Format: Journal
• Published: 2018
• Subjects: Agricultural and Biological Sciences
• Online Access: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84935917965&origin=inward; http://cmuir.cmu.ac.th/jspui/handle/6653943832/44318
• Institution: Chiang Mai University

© 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.