Mechanochemical Energy Transduction in Protein Motors

University Of California-Santa Cruz, Santa Cruz CA

Investigators

Abstract

Wang 0077971 ATP (adenosine triphosphate) is the universal chemical energy molecule in all living cells. ATP driven protein motors play a central role in many cell functions. For example, kinesin drives intracellular vesicle transportation and moves chromosomes during mitosis; myosin drives muscle contraction, and the V-ATPases regulate intracellular acidity. Understanding the operating principles of the ATP driven motors is crucial to comprehending intracellular protein transport and cell motility. Structural studies are providing the atomic details of motor proteins, and are revealing more information about the conformational changes associated with the chemical reactions they catalyze. Current experimental technologies permit measuring forces of a single protein motor with piconewton precision and motions with nanometer resolution. These advances, along with advances in mathematical modeling and computer power, make it possible to explore the mechanochemical energy transduction in molecular motors in unprecedented detail. In this project, the investigator and colleagues pursue the mathematical and physical issues that arose in the previous studies of F1 ATPase. These concern the molecular details of how protein motors should be modeled and what mathematical formulations are adequate for modeling them. In particular, the study focuses on the mechanism of force generation at the catalytic site during the ATP hydrolysis cycle. Resolution of this key process will illuminate the operating principles of this ATP driven motor, and likely other protein motors as well. To accommodate more sophisticated modeling, the investigator develops methods for analyzing protein structures and solving complex model equations. The results of these studies set the stage for modeling the mechanochemical energy transduction in myosin and kinesin dimers. The approach is to model the continuous stochastic motion of the motor using stochastic differential equations and couple these to the chemical reactions described by discrete Markov processes. The model equations are constructed from basic physical principles, structural data, and biochemical and biophysical measurements. These equations are then analyzed numerically. The hope is that this will lead to a unified view of ATP driven motors. To facilitate the fast growing field of biotechnology, it is necessary to deduce concise mechanisms for biological systems from experimental results. This requires the application of fundamental principles from the mathematical and physical sciences. The purpose of this interdisciplinary project is to study the mechanisms by which proteins use chemical energy to generate mechanical forces. In turn, these forces drive a wide variety of cellular processes essential to life. In all living cells, the universal chemical energy molecule is ATP (adenosine triphosphate). ATP is produced using the energy extracted from food, and the life of every cell depends on processes that are powered by ATP. For example, muscle contraction is directly driven by the ATP protein motor myosin. Therefore, understanding the operating principles of the ATP protein motors is central to comprehending the life of cells.