Charge effects on the fibril-forming peptide KTVIIE: 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 and a critical aspect of aggregation processes that underlie neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. There is a major problem in 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 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 method performs a replica exchange molecular dynamics 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, whereas the others do not. We examine dimer, trimer, and tetramer formation processes of these peptides, and compute high-accuracy potential of mean force association curves. The potential of mean forces 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.