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

@article{citeulike:2404065, 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 {beta}-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. 10.1529/biophysj.107.121061}, author = {Meli, Massimiliano and Morra, Giulia and Colombo, Giorgio}, citeulike-article-id = {2404065}, citeulike-linkout-0 = {http://dx.doi.org/10.1529/biophysj.107.121061}, citeulike-linkout-1 = {http://www.biophysj.org/cgi/content/abstract/94/11/4414}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18263661}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18263661}, day = {8}, doi = {10.1529/biophysj.107.121061}, journal = {Biophys. J.}, keywords = {short-peptides}, month = {February}, pages = {biophysj.107.121061+}, posted-at = {2008-11-29 18:10:25}, priority = {2}, title = {Investigating the Mechanism of Peptide Aggregation: Insights from Mixed MonteCarlo-Molecular Dynamics Simulations}, url = {http://dx.doi.org/10.1529/biophysj.107.121061}, year = {2008} }

TY - JOUR ID - citeulike:2404065 L3 - citeulike-article-id:2404065 N2 - 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 {beta}-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. 10.1529/biophysj.107.121061 JF - Biophys. J. TI - Investigating the Mechanism of Peptide Aggregation: Insights from Mixed MonteCarlo-Molecular Dynamics Simulations SP - biophysj.107.121061 KW - short-peptides AU - Meli, Massimiliano AU - Morra, Giulia AU - Colombo, Giorgio PY - 2008/02/08/ UR - http://dx.doi.org/10.1529/biophysj.107.121061 ER -