Dr. Govardhan Reddy

Solid State and Structural Chemistry Unit,

Indian Institute of Science

E-mail id: greddy[at]iisc.ac.in

Brief Bio-sketch:

Govardhan Reddy received his BS/MS degree in Chemistry from the Indian Insititute of Technology-Bombay. He graduated with a PhD in Chemistry from the University of Wisconsin-Madison working in simple liquids and polymer physics. Following his PhD, he joined the Biophysics group at the University of Maryland-College Park for his postdoctral fellowship. Currently, he is an Assistant Professor in the Solid State and Structural Chemistry Unit at Indian Institute of Science, Bengaluru.

COSOLVENT EFFECTS ON PROTEIN AGGREGATION

Cosolvents modulate the stability of protein conformations and exhibit contrasting effects on the kinetics of aggregation by globular proteins and intrinsically disordered proteins (IDPs). The growth of ordered protein aggregates, after the initial nucleation step is believed to proceed through a dock-lock mechanism. We have studied the effect of two denaturants (guanidinium chloride (GdmCl) and urea) and four protective osmolytes (trimethylamine N-oxide (TMAO), sucrose, sarcosine, and sorbitol) on the free energy surface (FES) of the dock-lock growth step of protein aggregation using a coarse-grained protein model and metadynamics simulations. We have used the proteins cSrc-SH3 and Aβ(9-40) as model systems representing globular proteins and IDPs, respectively. The effect of cosolvents on protein conformations is taken into account using the molecular transfer model (MTM). The computed FES shows that protective osmolytes stabilize the compact aggregates, while denaturants destabilize them for both cSrc-SH3 and Aβ(9-40). However, protective osmolytes increase the effective energy barrier for the multi-step domain swapped dimerization of cSrc-SH3, which is critical to the growth of protein aggregates by globular proteins, thus slowing down overall aggregation rate. Contrastingly, denaturants decrease the effective barrier height for cSrc-SH3 dimerization, and hence enhances the aggregation rate in globular proteins. The simulations further show that cSrc-SH3 monomers unfold before dimerization and the barrier to monomer unfolding regulates the effective rate of aggregation. In the case of IDP, Aβ(9-40), protective osmolytes decrease and denaturants increase the effective barriers in the dock-lock mechanism of fibril growth, leading to faster and slower growth kinetics, respectively.