Peptides in solution can assemble into a variety of nanoscale morphologies. On one hand, their aggregation is implicated in famous amyloid diseases, including diabetes and Alzheimer’s, and remains a leading problem in the development of bio-therapeutics. On the other, these systems have become exceptionally versatile platforms for new nanomaterials that self-assemble in response to cues spanning temperature, pH, salt, solvent, and chemical additives. While it has been well-established that peptides with more hydrophobic sequences tend to have higher aggregation propensities and rates, there are puzzling complexities beyond this first-order picture. In particular, de la Paz et al. found that a number of de novo designed peptides form fibrils only if the total net charge of the molecule is ±1 . They showed that neutral or higher effective charges on molecules often prevent fibril formation. The hydrophobic interaction and the ±1 charge effect can therefore both be considered as possible self-assembly stabilization factors, in contrast to the much simpler hydrophobic-centric view and the idea that electrostatic and hydrophobic interactions are in competition during assembly.
Here, we use molecular simulations of experimentally-characterized sequence families to understand the origins of electrostatic stabilization of peptide oligomers and its interaction with hydrophobic driving forces. We first use a new, two-dimensional replica exchange approach to compute to superb accuracy the free energy upon formation of small peptide dimer, trimer, and tetramer oligomers . The method couples an umbrella-sampling strategy with the usual multiple temperature cascade so as to achieve extensive exploration of conformational transitions and the entire association-dissociation reaction coordinate. Our results suggest an unexpected mechanism by which monovalent peptide sequences give rise to increased oligomer stability, relative to net uncharged or divalent ones: namely, the emergence in higher-order oligomers of stabilization forces that are entropic in nature, increasing fluctuations in the bound state. In addition, we compare these all-atom calculations to the behavior of much simpler, coarse-grained bead-spring peptide models. We find that microscopic signatures of hydrophobicity, such as water density fluctuations, do a good job of predicting sequence and charge effects of dimer formation free energies in these models.
 De la Paz, M. L., K. Goldie, J. Zurdo, E. Lacroix, C. M. Dobson, A. Hoenger, and L. Serrano. 2002. De novo designed peptide-based amyloid fibrils. PNAS. 99:16052-16057
 Gee, J. and M. S. Shell. 2011. Two-dimensional replica exchange approach for peptide-peptide interactions. J. Chem. Phys. 134:064112
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