Conformational distributions of isolated myosin motor domains encode their mechanochemical properties

Abstract

Myosin motor domains perform an extraordinary diversity of biological functions despite sharing a common mechanochemical cycle. Motors are adapted to their function, in part, by tuning the thermodynamics and kinetics of steps in this cycle. However, it remains unclear how sequence encodes these differences, since biochemically distinct motors often have nearly indistinguishable crystal structures. We hypothesized that sequences produce distinct biochemical phenotypes by modulating the relative probabilities of an ensemble of conformations primed for different functional roles. To test this hypothesis, we modeled the distribution of conformations for twelve myosin motor domains by building Markov state models (MSMs) from an unprecedented two milliseconds of all-atom, explicit-solvent molecular dynamics simulations. Comparing motors reveals shifts in the balance between nucleotide-favorable and nucleotide-unfavorable P-loop conformations that predict experimentally-measured duty ratios and ADP release rates better than sequence or individual structures. This result demonstrates the power of an ensemble perspective for interrogating sequence-function relationships.Subject AreasBiochemistry and Chemical Biology, Structural Biology and Molecular Physics

Atomistic Basis of Force Generation, Translocation, and Coordination in a Viral Genome Packaging Motor

“…This prevented ADP from accessing energetically favorable hydrogen bonding with the Walker A motif, reducing overall nucleotide affinity and likely precipitating complete dissociation of ADP from the active site. This phenomena has been characterized in myosin, where propensity of the Walker A motif to adopt a pose that is not receptive to β-phosphate hydrogen bonding is reported to be a predictor of ADP release rates 36 .…”

“…This prevents ADP from accessing energetically favorable hydrogen bonding with the Walker A motif, reducing overall nucleotide affinity and likely precipitating complete dissociation of ADP from the enzyme active site. This phenomena has been characterized in myosin motors (Porter et al, 2020), where propensity of Figure 3: ADP-release is promoted by a trans-acting exchange residue. ADP unbinding is characterized by dissociation of the β-phosphate from the cis-acting Walker A Lys32 (interaction shown left panel) and concomitant association (time-evolved distance shwon middle panel) of the β-phosphate to trans-acting Arg177 (interaction shown right panel), which is implicated as being the exchange residue.…”

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

“…[13][14][15] to the connection between phenotype and genotype. [16][17][18] Translational applications have included new means to combat antimicrobial resistance, Ebola virus, and SFTS virus. [19][20][21] Figure 1: Summary of Folding@home's computational power.…”

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

“…Folding@home enables anyone with a computer and an Internet connection to contribute to biomedical research by volunteering to run small chunks of simulation called 'work units' that are used to build maps of protein dynamics. The project has provided insight into diverse topics ranging from protein folding to signalling mechanisms [22][23][24] to the connection between phenotype and genotype [25][26][27] . Translational applications have included new means to combat antimicrobial resistance, Ebola virus and SFTS virus [28][29][30] .…”