The evolution of circulating viruses is shaped by their need to evade antibody response, which mainly targets the viral spike. Because of the high density of spikes on the viral surface, not all antigenic sites are targeted equally by antibodies. We offer here a geometry-based approach to predict and rank the probability of surface residues of SARS spike (S protein) and influenza H1N1 spike (hemagglutinin) to acquire antibody-escaping mutations utilizing in-silico models of viral structure. We used coarse-grained MD simulations to estimate the on-rate (targeting) of an antibody model to surface residues of the spike protein. Analyzing publicly available sequences, we found that spike surface sequence diversity of the pre-pandemic seasonal influenza H1N1 and the sarbecovirus subgenus highly correlates with our model prediction of antibody targeting. In particular, we identified an antibody-targeting gradient, which matches a mutability gradient along the main axis of the spike. This identifies the role of viral surface geometry in shaping the evolution of circulating viruses. For the 2009 H1N1 and SARS-CoV-2 pandemics, a mutability gradient along the main axis of the spike was not observed. Our model further allowed us to identify key residues of the SARS-CoV-2 spike at which antibody escape mutations have now occurred. Therefore, it can inform of the likely functional role of observed mutations and predict at which residues antibody-escaping mutation might arise. Author summary The immune system responds to viruses by making neutralizing antibodies to regions of the viral spike protein, which mutates to escape. To inform vaccine design and understand how the fitness landscape of the viral spike changes over time, it is necessary to identify and quantify the factors directing its evolution. Based on the 3D structure of the viral surface and spike as captured with Cryo-EM and crystallography, we aimed to create a coarse-grained model for the effect of antibodies in forcing surface residues of the spike to mutate. We found that for pre-pandemic influenza (hemagglutinin) and the corona sarbecovirus subgenus (S protein), the location of a residue on the spike protein, which modulates its accessibility to antibodies, highly correlates with its propensity to mutate. Hence, a mechanistic approach can be used to identify aspects of viral spike sequence diversity related to antibody escape.
【초록키워드】 viruses, neutralizing antibody, Evolution, antibodies, SARS-CoV-2, Mutation, S protein, spike, antibody, Influenza, Antibody Response, Vaccine design, immune system, virus, MD simulation, Probability, Region, Pandemics, target, H1N1, mutability, in-silico, 3D structure, change, predict, Antibody escape mutation, sarbecovirus, Seasonal influenza, viral spike protein, Factor, viral surface, residue, sequence, circulating, viral spike, offer, approach, identify, occurred, can be used, functional, the spike protein, modulate, evade, respond, mutate, antigenic site, the SARS-CoV-2, 【제목키워드】 Evolution, coronavirus, antibody, Influenza,