Vivek Vasandani

Amyloid fibrils are large multimeric assemblies that have been found to accumulate in several brain regions of patients suffering from Parkinson’s, Multiple Systems Atrophy, Alzheimer’s, Chronic Traumatic Encephalopathy, Prion, and other neurological diseases. These assemblies have been found to be toxic in vivo and in vitro and correlate with the progression of their associated diseases. The recent development of cryo-EM technology resulted in the publication of over 100 different fibril structures. These protein structures are static and their dynamics via simulations remain understudied. In this study, we used full-atom molecular dynamics (MD) to investigate the behavior of 27 amyloid protofilaments from 7 different proteins related to neurodegenerative diseases. MD simulations provide a powerful platform to efficiently understand protofilament dynamics within a physiological replicative solution. Each protofilament was simulated using the CHARMM36 force field in triplicate for 100 ns, yielding a total of 8.1 μs of run time. We found that the protofilaments show distinct global root mean square deviations (RMSD) from their original structure throughout the 100 ns of run time. In addition, the majority of protofilaments display RMSD polarity between their two ends, which has been hypothesized to influence directionality of fibril elongation. Finally, we found that most of these neurodegeneration-related amyloid fibrils contain cavities that span the fibril z-axis. These cavities are permeated by water molecules which form extensive hydrogen bond networks with inward-facing polar amino acid side chains and backbone amides. We hypothesize that these cavity-water interactions are stabilizing and critical for the elongation of amyloid fibrils.