Identifying Strain-Driven Mechanisms of Surface Layer Disassembly Through Multiscale Modeling

Surface layer proteins (SLPs) are multi-domain proteins that self-assemble into multi-functional paracrystalline lattices on the surface of many bacteria and archaea. Recently, the SLP of B. anthracis was found to be a virulence factor that could be targeted with camelid nanobodies, disassembling the lattice and disarming the pathogen. However, more than half of known SLP-binding nanobodies did not cause lattice disassembly despite binding strongly to the same site as the SLP-inhibitory nanobodies, suggesting that binding affinity cannot fully account for the mechanism of disassembly. We hypothesize that inhibitory nanobodies induce greater strain onto the lattice than their non-inhibitory counterparts, causing lattice disassembly. We employ multiscale molecular dynamics and machine learning to identify restricted motions correlated with disassembly, and assess strain induced by these motions in a computational depolymerization assay. We will present our findings on the mechanical basis of nanobody-induced disassembly, mechanics-driven nanobody design in B. anthracis, and discuss implications for other antibiotic-resistant SLP-bearing pathogens.