Thermodynamics and dynamics of amyloid peptide oligomerization are sequence dependent |
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Authors: | Yan Lu Philippe Derreumaux Zhi Guo Normand Mousseau Guanghong Wei |
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Institution: | 1. Department of Physics and National Key Surface Physics Laboratory, Fudan University, 220 Handan Road, Shanghai, 200433, China;2. Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie Physico‐Chimique et Université Paris 7,13 rue Pierre et Marie Curie, 75005 Paris, France;3. Département de Physique and GéPROM, Université de Montréal, C.P. 6128, succursale centre‐ville, Montréal (Québec), Canada |
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Abstract: | Aggregation of the full‐length amyloid‐β (Aβ) and β2‐microglobulin (β2m) proteins is associated with Alzheimer's disease and dialysis‐related amyloidosis, respectively. This assembly process is not restricted to full‐length proteins, however, many short peptides also assemble into amyloid fibrils in vitro. Remarkably, the kinetics of amyloid‐fibril formation of all these molecules is generally described by a nucleation‐polymerization process characterized by a lag phase associated with the formation of a nucleus, after which fibril elongation occurs rapidly. In this study, we report using long molecular dynamics simulations with the OPEP coarse‐grained force field, the thermodynamics and dynamics of the octamerization for two amyloid 7‐residue peptides: the β2m83‐89 NHVTLSQ and Aβ16‐22 KLVFFAE fragments. Based on multiple trajectories run at 310 K, totaling 2.2 μs (β2m83‐89) and 4.8 μs (Aβ16‐22) and starting from random configurations and orientations of the chains, we find that the two peptides not only share common but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in Aβ16‐22 with respect to β2m83‐89 impacts the thermodynamics by reducing the population of bilayer β‐sheet assemblies. Higher hydrophobicity is also found to slow down the dynamics of β‐sheet formation by enhancing the averaged lifetime of all configuration types (CT) and by reducing the complexity of the CT transition probability matrix. Proteins 2009. © 2008 Wiley‐Liss, Inc. |
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Keywords: | peptide aggregation β ‐sheet hydrophobicity molecular dynamics simulations coarse‐grained force field free‐energy surface connectivity length β 2m83‐89 Aβ 16‐22 |
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