The mechanism of folding of proteins to their native structure is a subject of significant interest in biology. Proteins perform most of the molecular level functions in the cell. In addition, proteins are nanoscale molecular machines that can perform tasks important for biotechnology applications. It is well known that the marginal stability of proteins can be altered by changing solvent conditions, such as application of pressure, or addition of co-solvents. Computer simulations can provide an atomic level picture of the mechanisms by which solvent (mostly water), co-solvents, and physical effects, such as pressure and temperature, affect protein stability. The combined use of enhanced sampling methods and parallel computing enable the study of protein folding/unfolding equilibrium and dynamics. The objective of this project is to study the folding/unfolding equilibrium and kinetics of model proteins with increased degree of complexity. The simulations will explore the effects of co-solvents and hydrostatic pressure on the transition states and will help understand the effect of solvent in determining the transition state of proteins and will provide a measure of the folding/unfolding activation volumes. These calculations will be done on model proteins that fold in the microsecond timescale and for which there is ample kinetics and thermodynamics experimental data available. In addition to folding, this project will explore the functional dynamics of the proteins - that is, correlate the existence of sub-states in the energy landscape with functional states of the proteins. The overall goal is to examine the equilibrium folding/unfolding, the energy landscape, the folding kinetics and dynamics of protein domains involved in protein-protein interactions and switching. These proteins fold in the microsecond to 100 microsecond timescales. The kinetics and functional dynamics of these proteins will be studied using Markov state models built from a very large number of independent simulations. Theories related to the allosteric effect in proteins will be tested.
This research is interdisciplinary in nature and includes the use of physical and computational methods to describe basic steps in the functioning of biological models. An important element of this project is the training of scientists with expertise in physics, biology and computational methods. This training will be done with students at various levels of education - including high school, undergraduate and graduate students, and postdoctoral fellows. Another equally important element of this research is the commitment to enhance participation of underrepresented groups in research. The PI's laboratory has continuously hosted and will continue to host minority and women undergraduates doing research in the group. Many of these students have now obtained PhDs or are pursuing graduate studies. This project is jointly supported by Molecular Biophysics in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences and the Physics of Living Systems Program in the Division of Physics in the Mathematical and Physical Sciences Directorate.
