Molecular insights into the binding affinity and specificity of the hemagglutinin cleavage loop from four highly pathogenic H5N1 isolates towards the proprotein convertase furin |
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Authors: | Panita Kongsune Thanyada Rungrotmongkol Nadtanet Nunthaboot Pathumwadee Yotmanee Pornthep Sompornpisut Yong Poovorawan Peter Wolschann and Supot Hannongbua |
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Institution: | (1) Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand;(2) Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand;(3) Department of Chemistry, Faculty of Science, Mahasarakham University, Mahasarakham, 44150, Thailand;(4) Center of Excellence in Clinical Virology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand;(5) Institute of Theoretical Chemistry, University of Vienna, 1090 Vienna, Austria;(6) Center of Excellence for Petroleum, Petrochemicals, and Advanced Materials, Chulalongkorn University, Bangkok, 10330, Thailand; |
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Abstract: | Abstract The furin (FR) complex with each of four different sequences of hemagglutinin from the highly pathogenic H5N1 strains (HPH5),
which were identified during the 2004–2010 influenza outbreaks in Thailand, were evaluated by molecular dynamics simulations,
so as to compare the specificity and recognition of the enzyme–substrate binding. Relative to the conventional HPH5 inserted
(H5Sq1, RERRRKKR), the S5-R or S6-R arginine residue is replaced by the smaller lysine in the H5Sq2 (RERKRKKR) and H5Sq3 (REKRRKKR) strains, respectively, whereas the S3-K lysine residue is deleted in H5Sq4 (RERRR_KR). The molecular dynamics results
of the intermolecular interactions, in terms of hydrogen bonds and per-residue decomposition energy, between the substrate
and furin revealed that the deletion of the positively charged amino acid at the S3 position in H5Sq4 leads to a notably weaker
binding and specificity with the furin active site compared with that of FR–H5Sq1. A slight change in the substrate binding
was found in the FR–H5Sq2 and FR–H5Sq3 complexes as a result of the replacement of the arginine with the shorter side-chained
lysine (same positive charge). Altogether, the predicted binding free energy of the enzyme–substrate complexes was found to
be in the following order: FR–H5Sq1 < FR–H5Sq2 ~ FR–H5Sq3 ≪ FR–H5Sq4. |
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