Keywords: biomolecular dynamics; molecular landscapes; sample-based modeling; landscape reconstruction; dysfunction.
Starting with Sir Turing in 1952, decades of scientific enquiry have demonstrated how fundamental the form of matter and changes to form are to function and function modulation. The ability to see three-dimensional structures of biological molecules and catch them wiggling and jiggling their atoms to accommodate molecular partners has renewed focus on a structure-centric understanding of biomolecular function in molecular biology. A primary objective of research in my laboratory is the design of novel algorithmics for elucidating biomolecular structures and their rearrangements as fundamental to understanding (dys)function, cellular processes, our own biology, disease, and disease treatments. My laboratory has proposed and matured sample-based models that build increasingly-detailed representations of biomolecular energy landscapes that govern equilibrium structural dynamics. This work is instigating novel spatial data visualization and inference methods in order to harness landscape-embedded information about biomolecular function and dysfunction. I will demonstrate that these methods are allowing us to discover and categorize mechanisms via which pathogenic mutations alter protein dynamics and function in human disorders. In particular, as I will demonstrate on a key oncogene, this line of research is bringing us closer to simulating and learning in silico how pathogenic mutations alter biological activities in the diseased cell.