Molecular motors and switches lie at the heart of key biological processes, from the division and growth of cells to the muscular movement of organisms. Our approach to studying these fascinating nanomachines couples bioinformatics (to probe sequence-structure-function relationships); molecular dynamics (to investigate essential conformational changes); Brownian dynamics (for diffusional protein-protein encounters); and computer-aided drug design (for discovering novel therapeutics). I will describe two discoveries that exemplify the power of this approach. First, how it uncovered the importance of electrostatics in the motion of kinesin motors, and how this information enabled the rational design of mutant motors with tailored velocities. Second, how it revealed that the traditional 'induced fit� view for activating conformational changes in molecular switches should be replaced by a �conformational selection� model, and how this framework led to the discovery of novel small molecule Ras inhibitors.Images and animations related to this work can be found at: http://thegrantlab.org/

Biomolecular motors and switches: From machines to drugs

243rd National Meeting (2012)

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