Fawad Khan, Ashfaq Ahmad*, Abid Ali, Syed Shujait Ali and Tayyab Ur Rehman Pages 310 - 318 ( 9 )
Introduction: Dengue virus is among the most widespread mosquito-borne human pathogens with 5 different serotypes. A ratio of 3 to 7 structural and non-structural proteins is retained by the 10.7 kb viral RNA genome. The Dengue virus NS5, a non-structural and most conserved protein in the genome plays vital role in virus replication machinery. The C-terminal RNA-dependent RNA polymerase (RdRp) domain of NS5 has been solved experimentally in the canonical right handed conformation that comprises of 3 sub-domains namely finger, palm and thumb. The presence of different structural characteristics portray that RdRp adopts various conformation strategies to fulfill functional modes.
Methodology: To understand the molecular switches and signaling pattern that govern conformational functional features of NS5 RdRp domain, long-range dynamic by normal mode analysis coupled with comparative structure analysis and Insilico docking approaches were performed.
Results: Our findings state that palm and finger are role playing and flexible sub-domains whereas the C-terminus region of motif B influence signal transmittance and substrate binding. Different motifs of RdRp are trivial in direct conformational transition except two C-terminal residues of motif B (L608 and T611) which modulate path signals. Signalling path indicates that dynamic clusters regulate RdRp allosteric pathway where α10 and α20β6 loop of the finger and thumb sub-domains act as terminals in both directions. Besides, the catalytic site, α16 connects and relay conformational signals to α12 through β5α19 loop.
Conclusion: The occurrence of motif B in four dynamic clusters 1, 2, 6 and 7 strengthen our notion further corroborated that all motifs are trivial in direct conformational transition and motif B retains modulation of major conformation signals.
Non-structured protein 5, RdRp, dengue virus, long-rang dynamics, allosteric pathways.
Center of Biotechnology and Microbiology, University of Swat, Swat, KPK, Department of Biology, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, Department of Animal Sciences, Faculty of Biological Sciences, Quaid-i-Azam University Islamabad, Center of Biotechnology and Microbiology, University of Swat, Swat, KPK, Department of Microbiology, Institute of Basic Medical Sciences (IBMS), Khyber Medical University, Peshawar, KPK