Modeling Biomolecular Transport Processes

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Elston0075821 The broad goal of this project is to gain a mechanisticunderstanding of energy transduction in biomolecular transportprocesses. The project focuses on three specific systems: thebacterial flagellar motor, the motor protein dynein, and proteintranslocation systems found in membranes of the endoplasmicreticulum and mitochondria. While the biology involved in thesesystems is very different, the same mathematical techniques areapplicable for analyzing theoretical models of all three. Tomodel these systems requires the use of Langevin or stochasticdifferential equations. The randomness in these equations comesfrom two sources, thermal diffusion and chemical kinetics.Thermal fluctuations are characterized by the diffusioncoefficient, which can be measured experimentally, and many ofthe important reaction rates are known from biochemical studies.In addition to molecular collisions, electrostatic interactionsare the other dominant forces involved in these transportsystems. If available, structural data are used to determine therelevant electrostatic potentials. Once model equations for thesystems have been developed, numerical and analytical techniquesare used to compare their behavior with experimental data. Thefinal phase of the analysis is to use the mathematical models toproduce experimentally testable predictions. Biological molecular motors are nanometer-sized engines thatuse chemical energy to generate force. A well known molecularmotor is myosin, which is the protein responsible for musclecontraction. Other examples include the flagellar motor, which isused by bacteria for swimming, and dynein, which produces theforce necessary for cilia motion. The broad goal of this projectis to gain a mechanistic understanding of force generation inboth these systems. Current experimental techniques are allowingbiophysicists to study molecular motors at the single moleculelevel, thereby allowing the mechanical properties of motorproteins to be measured. These new physical data in conjunctionwith structural data provide the impetus for renewed theoreticalinvestigations into molecular motor function. An important reasonfor performing a mathematical analysis of force generation isthat it allows a quantitative comparison between experimentaldata and model behavior to be made. The results of such acomparison not only are important for model validation, but alsocan be used to uncover errors in the assumptions underlying themodel. However, the significance of mathematical modeling goesbeyond model validation and lies in its predictive power. Once atheoretical model has been developed that is consistent withcurrent experimental data, it is straightforward to extend theanalysis to include situations that have not yet beeninvestigated in the laboratory. If model predictions are borneout by experiment, further confidence in the reality of the modelis gained. For the systems under consideration in this project,this means a mechanistic understanding of force generation hasbeen achieved. From a technological standpoint, the results ofthese investigations should be relevant for designing andfabricating manmade nanomachines.