Rational drug design and understanding of how mutations cause disease are largely based on the hypothesis
that a protein's sequence determines its structure, which determines its function. However, designing drugs and
interpreting new variants remain difficult, suggesting there is a missing factor in this sequence-structure-function
paradigm. There is good reason to believe that a sequence-ensemble-function paradigm that better accounts for
the fact that proteins are not rigid bodies, but are dynamic entities that are endlessly hopping through a set of
different structures (called an ensemble) would be far more powerful. However, realizing this potential has been
slow because it is even harder to get an atomically-detailed picture of an entire ensemble than a single protein
structure. The PI and his lab have been developing tools that combine atomically-detailed computer simulations,
biophysical experiments, and machine learning to overcome this challenge. They have made significant progress
on relatively small proteins with limited dynamics, enabling a deeper understanding of how mutations modulate
function and the design of new drug-like molecules for controlling function. The objective of this work is to test
the applicability of these tools to much larger and more complicated proteins that are of significant importance
in both fundamental biology and drug design, myosin motors. Myosins are responsible for a broad range of
biological functions, from muscle contraction to hearing. As a result, they are important targets for treating
diseases ranging from heart failure to parasitic infections. To function, myosins must undergo a complex series
of structural changes. The PI and his lab will test whether their tools for accounting for these extensive dynamics
enable more accurate predictions of sequence-function relationships and the rational design of new drug-like
molecules for controlling motor function. They will focus on ß-cardiac myosin because of its importance in heart
disease and the myosin 1 family of motors because its members have highly diverse biological functions but it
remains unclear how mutations tune the motor's behavior for all these different purposes. The lab will design
new myosin variants and allosteric modulators as a stringent test of their insights. Success will enable future
myosin drug discovery and application of these tools to other proteins.