Sequence Landscapes In Peptide Oligomerization and Self-Assembly

Thursday, October 20, 2011: 1:02 PM
103 D (Minneapolis Convention Center)
M. Scott Shell, Tommy Foley and Joo-Hyun Jeon, Department of Chemical Engineering, University of California Santa Barbara, Santa Barbara, CA

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 [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 [2].  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.

[1] 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

[2] 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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