Natural variants with 2D correlation genetics identify domains coordinating sarcomere proteins during contraction

Abstract

Muscle proteins assemble in a sarcomere then by coordinated action produce contraction force to shorten muscle. In the human heart ventriculum, cardiac myosin motor ({beta}mys) repetitively converts ATP free energy into work. Cardiac myosin binding protein C (MYBPC3) in complex with {beta}mys regulates contraction power generation. Their bimolecular complex {beta}mys/MYBPC3 models the contractile system and is used here to study protein coupling. The database for single nucleotide variants (SNVs) in {beta}mys and MYBPC3 surveys human populations worldwide. It consistently records SNV physical characteristics including substituted residue location in the protein functional domain, the side chain substitution, substitution frequency, and human population group, but inconsistently records SNV implicated phenotype and pathology outcomes. A selected consistent subset of the data trains and validates a feed-forward neural network modeling the contraction mechanism. The full database is completed using the model then interpreted probabilistically with a discrete Bayes network to give the SNV probability for a functional domain location given pathogenicity and human population. Co-domains, intra-protein domains coupling {beta}mys and MYBPC3, are identified by their population correlated SNV probability product for given pathogenicity. Divergent genetics in human populations identify co-domain correlates in this method called 2D correlation genetics. Pathogenic and benign SNV data identify three critical regulatory sites, two in MYBPC3 with links to several domains across the {beta}mys motor, and, one in {beta}mys with links to the known MYBPC3 regulatory domain. Critical sites in MYBPC3 are hinges (one known another proposed) sterically enabling regulatory interactions with {beta}mys. The critical site in {beta}mys is the actin binding C-loop, a contact sensor triggering actin-activated myosin ATPase and contraction velocity modulator coordinating also with actin bound tropomyosin. C-loop and MYBPC3 regulatory domain linkage potentially impacts multiple functions across the contractile system. Identification of co-domains in a binary protein complex implies a capacity to estimate spatial proximity constraints for specific dynamic protein interactions in vivo opening another avenue for protein complex structure/function determination.