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

作者：Yotmanee Pathumwadee; Rungrotmongkol Thanyada; Wichapong Kanin; Choi Sy Bing; Wahab Habibah A^*; Kungwan Nawee; Hannongbua Supot

来源：Journal of Molecular Graphics and Modelling, 2015, 60: 24-33.

DOI：10.1016/j.jmgm.2015.05.008

• Dengue virus
• NS2B/NS3 protease
• Polypeptide
• Pathogenic
• Molecular dynamics

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 P1 and P2 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 P1 reacting center of the capsid, intNS3, 2A/2B and 4B/5 peptides. These results led to the order of absolute binding freeenergy (Delta G(bind)) 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.

• 出版日期2015-7