To obtain a deeper understanding of protein folding, function, and disease-causing aggregation, I have exploited both experimental and theoretical methods of physical chemistry. Nanosecond lasers were used to investigate the kinetics of early events in protein folding and of ultrafast folding proteins. Nanosecond photodissociation of the carbon monoxide complex was used to study dynamics and kinetics of conformational relaxation in myoglobin and hemoglobin. This method was also applied to the study of aggregation kinetics of the mutant hemoglobin S that forms fibers responsible for sickle cell disease. Theoretical models have been developed to explain the major experimental results in all three areas: (1) an Ising-like model in which the protein folding mechanism is dominated by residue-residue interactions present in the native folded structure that explains a wide range of equilibrium and kinetic results, (2) a model that explains stretched exponential conformational relaxation kinetics and the simplest extension of the allosteric model of Monod, Wyman, and Changeux to include tertiary conformational pre-equilibria that remove deficiencies in their model and explain a series of unusual photolysis results for hemoglobin embedded in silica gels that trap unstable protein conformations, and (3) a double nucleation model with autocatalytic secondary nucleation to explain the lag phase and its large concentration dependence - up to 40th power. The model also explains the concentration dependence of up to 80th power for the primary nucleation rate as arising from a combination of a large nucleus size and the concentration dependence of the large activity coefficients due to excluded volume effects in the concentrated protein solutions (80 is not a typo). Importantly, the double nucleation mechanism has been invoked to explain the peptide aggregation kinetics responsible for Alzheimer’s disease.

Physical chemistry of protein folding, function, and aggregation

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.