Structural effects of ALS-associated mutations on profilin.

Abstract

Amyotrophic Lateral Sclerosis (ALS), known as Lou Gehrig's disease, which has been on the rise (approximately 31000 patients in the USA, according to CDC), has been associated with specific mutations on Profilin, a protein with distinct binding sites for both poly-L-proline (PLP) and Actin. Here in this computational study, we have investigated the effect of a few of these mutations inducing conformational differences and alteration of secondary structures that could be the molecular reason behind the ALS. Among a few potential mutations associated with the disease, we have investigated the effect of G118V and T109M mutations and their combination in the conformational changes of Profilin and Actin in the presence of PLP. Using close to 30 microseconds of all-atom molecular dynamics simulations across 16 systems of study composed of Profilin, Actin, and PLP, we have identified intermolecular interactions that could be among the main reasons for conformational differences between wild-type Profilin and mutants and potentially the reasons for the ALS in the molecular level due to the mutations. Our findings help to gain a better molecular-level understanding of ALS. We can use the plethora of structural and conformational information and intermolecular interactions to design novel therapeutics for the disease.