Histidine 73 methylation coordinates β-actin plasticity in response to key environmental factors

Although β -actin is one of only two ubiquitously expressed actin isoforms present in all cells, it remains understudied biochemically due to technical challenges associated with protein production and purification. In particular the importance of histidine 73 (H73) methylation of β -actin remains unclear. Here, we employed molecular dynamics simulations using an advanced method that couples a polarizable force field to large scale adaptive sampling to achieve higher level of interatomic interaction accuracy when compared to classical atomic force fields. This methodology enabled us to investigate the effect of H73 methylation on the plasticity of both β -actin monomers (G-actin) and filaments (F-actin) and capture how subtle conformational changes are relevant to β -actin function. We uncovered that H73 methylation enhances the opening of the nucleotide binding cleft and modifies allosteric paths linking subdomains 2 and 4 (SD2 and SD4) of actin. We showed that in F-actin H73 methylation affects the opening of a backdoor and limits the release of the inorganic phosphate, as confirmed by biochemical assays. We also observed that effects of H73 methylation are modulated by the type of nucleotide bound in the actin cavity and ions surrounding the protein. Taken together, these results shed new light onto how H73 methylation regulates β -actin plasticity and coordinates impact of several key environmental factors. ### Competing Interest Statement P. R., L. L., and J.-P. P. are co-founders and shareholders of Qubit Pharmaceuticals.