ИСТИНА

The dynamic characteristics of the protein binding pockets can play an important role searching for new inhibitors as promising medical drugs. Potential compounds selected according to their influence on a dynamic protein structure might have a higher activity and selectivity by overcoming disadvantageous interactions within a pocket at its structural rearrangements. In case of hemagglutinin a structural rearrangement is responsible for the fusion of virus and host cell membranes, followed by the spread of viral ribonucleoproteins into a healthy cell. It is formed by the parts of the polypeptide chain that undergo significant conformational changes at the membranes fusion. Basing on X-ray crystallography data it was suggested [1] that binding of the three umifenovir molecules in three static hemagglutinin binding sites S1 can create a network of non-covalent interactions that prevent hemagglutinin restructuring at fusion to the host cell membrane. Thus, the possible stabilization of the protein structure due to binding of compounds in S1 binding site can make it an attractive target for comprehensive search of effective drugs against Influenza virus.In this work we have investigated a dynamic behavior of S1 hemagglutinin binding sites in H3N2 and H7N9 Influenza subtypes. We have calculated the energy profiles of these pockets depending on the changes in S1 volumes using enhanced sampling by metadynamics what allowed to accelerate accumulation of statistics of rare events while controlling various system characteristics using the so-called collective variables (CV). In the case of the H3N2, the S1 volume was used as the only CV specified by the presence of water molecules within a pocket studying its dynamics in an aqueous solution. In case of H7N9 hemagglutinin the S1 binding site is known to possess a closed (without inhibitor) and an open (inhibitor bound) conformation that is determined by the position of Arg54 in the chain B: therefore additional CV taking into account positioning of Arg54 was used to perform the metadynamics. As a result free energy maps were obtained and allowed to characterize the S1 volume with a minimum energy and identify amino acid residues foremost responsible for the dynamic volume change. The sampled S1 pocket structures might serve as a framework searching for new compounds able to bind in a S1 site effectively and impair structural rearrangements of the Influenza hemagglutinin. The research was carried out using the equipment of the shared research facilities of HPC computing resources at Lomonosov Moscow State University [2]. The study was supported by RFBR (grant 18-315-00390)