Investigating the Mechanism of Peptide Aggregation: Insights from Mixed MonteCarlo-Molecular Dynamics Simulations

¹ Istituto di Chimica del Riconoscimento Molecolare, CNR

^* To whom correspondence should be addressed. E-mail: g.colombo{at}icrm.cnr.it.

Submitted on August 31, 2007
Revised on October 26, 2007
Accepted on 11 December 2007

	Abstract

The early stages of peptide aggregation are currently not accessible by experimental techniques at atomic resolution. In this paper, we address this problem through the application of a mixed simulation scheme in which a preliminary coarse-grained Monte Carlo (MC) analysis of the free energy landscape is used to identify representative conformations of the aggregates and subsequent all-atom molecular dynamics (MD) simulations are used to analyze in detail possible pathways for the stabilization of oligomers. This protocol was applied to systems consisting of multiple copies of the model peptide GNNQQNY, whose detailed structure in the aggregated state has been recently solved [Nelson et al. Nature 2005, 435, 773-8]. The analysis of the various trajectories provides dynamical and structural insight into the details of aggregation. In particular, the simulations suggest a hierarchical mechanism characterized by the initial formation of stable parallel -sheet dimers and identify the formation of the polar zipper motif as a fundamental feature for the stabilization of initial oligomers. Simulation results are consistent with experimentally derived observations and provide an atomically detailed view of the putative initial stages of fibril formation.

Key Words: aggregation, amyloid, fibril formation, molecular dynamics, self-assembly, simulations

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