Charge Effects on the Fibril-Forming Peptide KTVIIE: A Two-Dimensional Replica Exchange Simulation Study

Abstract

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 þ TVIIE À , K þ TVIIE, and þ K þ TVIIE. Interestingly, experiments show that only the monovalent peptide, K þ 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.

Solution effects on the self‐association of a water‐soluble peptoid

“…Additionally, we reasoned that new assembly sizes and structures might be accessible in the absence of the positive charge on the N ‐terminus of 1 . The absence of this terminal charge promoted assembly of peptides at high pH into fibrils by enhancing conformational degeneracy . A peptide with negatively charged side chains and neutral N ‐terminus was able to assemble in parallel or antiparallel fashion, and this provided an entropic stabilization of the assembly.…”

Enhancing Constant-pH Simulation in Explicit Solvent with a Two-Dimensional Replica Exchange Method

“…This can be readily obtained by using eq 16 as follows: (42) where N is the number of configurations in Γ 0 , x i ∈ Γ 0 , n is a protonation-state vector where n j = 1 if the jth residue is deprotonated and otherwise n j = 0, E(x i ,n) is the potential energy of a protonation state n at a conformation x i , and E offset (n) is the offset energy of the protonation state n.…”

Alpha-crystallin-derived peptides as therapeutic chaperones

“…Phe71 is a highly conserved residue in sHSPs, across many species (Table 1). It is well documented that the addition of charged amino acids to the peptides can produce dramatically different levels of activity [58]. We also attempted to add additional residues at either the N- or C-terminal, or both termini, to create chaperone peptides with increased activity.…”