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Influenza virus hemagglutinin (HA) plays a key role in the process of virus and the host cell membranes fusion. Hemagglutinin includes lectin (HA1) and stem (HA2) domains. The stem domain of the HA is highly conservative compared to lectin domain. The binding of inhibitors in the hemagglutinin stem domain has been studied and X-ray structures of HA complexes with tert-butyl hydroquinone, N-cyclohexyltaurine, and the commercial drug umifenovir have been reported recently. It is hypothesized that the binding of these compounds could inhibit the structural rearrangement of the HA2 domain in the acidic environment of the endosome during virus entry to host cell and block the release of the influenza genetic material into the cell cytoplasm. In silico study of the hemagglutinin stem domain rearrangement can provide a detailed understanding of this process. The early stage of the H3N2 influenza virus hemagglutinin stem domain structural rearrangement was studied in neutral and acidic conditions. All computer simulations were carried out for the entire HA2 domain. The protonation states of the amino acid residues at neutral and acidic pH were calculated using the PROPKA3 program. The additional constant-pH molecular dynamics simulation has been performed to refine protonation states for Glu120, Glu128, Glu131 and Asp132. Analysis of the electrostatic potential projections given by APBStools for pH 7 and 5 onto the hemagglutinin surface revealed change of charge at acidic conditions compared to neutral pH: the large interface area between three HA monomers near C-terminus switches its charge to positive. This region is formed by three symmetric parts, consisting of residues from 106 to 171. As a result of such charge changing the fusion peptide located in this region at the positively charged N-terminus is released, which initiates the hemagglutinin rearrangement process. Molecular dynamics in tandem with metadynamics was used to simulate the hemagglutinin HA2 domain structural rearrangement. The initial rearrangement stage is characterized by conformational changes in the C-terminal region of HA as well as changes in the position of the HA monomers side parts (residue 1 to 75), which are subsequently added as α-helices to stable regions (residue 76 to 105). The radius of gyration (RG) for all atoms of 106 to 171 amino acid residues was used as the first collective variable (CV) for the metadynamics to describe the rearrangement of the C-terminus area. The increasing RG indicates the increasing distance between three symmetric parts of HA2, which numerically describes this part of the process without any other variables. The distance (Dcom) between the centers of mass of the side α-helix from 37 to 56 residues and the common center of mass of α-helices from 97 to 115 residues of two adjacent monomers has been chosen as appropriate second CV of the process. The free energy surfaces of the HA2 domain initial stage rearrangement were obtained after metadynamics simulation with the selected CV (RG and Dcom) at pH 7 and 5. A comparison of the surfaces at neutral and acidic pH showed that changes in the conformation of the HA stem domain occur arbitrarily only after a change in the charge at the interface between monomers at low pH. The developed modeling pipeline for studying the early stage of influenza virus hemagglutinin stem domain rearrangement using metadynamics makes it possible to simulate the process under various pH conditions. The proposed simulation scheme will allow studying the early rearrangement of hemagglutinin in complex with potential inhibitors and evaluating their effectiveness in the rational design and/or testing candidate molecules based on virtual screening.