(117g) Charge Effects On the Fibril-Forming Peptide KΤVΙΙΕ: A Two-Dimensional Replica Exchange Simulation Study

The assembly of peptides into ordered nanostructures is increasingly recognized as both a bioengineering tool for generating new materials as well as a critical aspect of aggregation processes that underlie neurological diseases such as Alzheimer’s, Parkinson’s and Huntington’s. A major problem is understanding how extremely subtle sequence changes can lead to profound and often unexpected differences in self-assembly behavior. To better delineate the complex interplay of different microscopic driving forces in such cases, we develop a novel methodology to quantify and compare the propensity of different peptide sequences to form small oligomers during early self-assembly stages. This Umbrella Sampling Replica Exchange Molecular Dynamics (UREMD) method performs a REMD simulation along peptide association reaction coordinates using umbrella restraints.

With this method, we study a set of sequence-similar peptides that differ in net charge: K+TVIIE-, K+TVIIE, and +K+TVIIE. Interestingly, experiments show that only the monovalent peptide, K+TVIIE, forms fibrils, while the others do not. We examine dimer, trimer, and tetramer formation processes of these peptides, and compute high-accuracy potential of mean force (PMF) association curves. The PMFs recapitulate a higher stability and equilibrium constant of the fibril-forming peptide, similar to experiment, but reveal that entropic contributions to association free energies can play a surprisingly significant role. The simulations also show behavior reminiscent of experimental aggregate polymorphism, revealed in multiple stable conformational states and association pathways. Our results suggest that sequence changes can have significant effects on self-assembly through not only direct peptide-peptide interactions but conformational entropies and degeneracies as well.

We also use this method to study the self-assembly of a diphenylalanine peptide that was recently found to form nanotubes in aqueous solution. To address the potential role of electrostatic interactions in this assembly process, we compare UREMD results of a zwitterionic diphenylalanine dimer with that of a modified non-charged diphenylalanine dimer.