Complexity in understanding allosteric stimulation of the hemagglutinin-neuraminidase (HN) protein of paramyxoviruses by host sialic acids (SIAs) stems from (1) unavailability of structure in its SIA-bound state and (2) the observation that this process is temperature sensitive. To consider simultaneously SIA's effect on structure and thermal fluctuations, we use molecular dynamics and simulate the dimeric form of the Newcastle disease virus HN. We find that SIA induces only minor structural changes in individual monomers, yet it reorients dimer interface by 10°. Interface reorientation is accompanied by constriction of SIA binding groove and enhanced fluctuations of interfacial residues that disrupt hydrophobic interactions and favor creation of new salt bridges. Supervised machine learning analysis of non-equilibrium data reveals that the allosteric signal is not formed from a directed sequence of these events. Altogether, we propose a detailed model of the initial events of allosteric stimulation, consistent with experiments on engineered mutations.
Keywords: Newcastle disease virus; allosteric signaling; conformational ensembles; dynamic allostery; machine learning analysis; molecular dynamics; paramyxovirus entry; protein-ligand interactions; protein-protein interactions; thermal fluctuations.
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