Molecular dynamics simulation of the aggregation of the core-recognition motif of the islet amyloid polypeptide in explicit water

Giorgio Colombo 1 5 *, Isabella Daidone 2, Ehud Gazit 3, Andrea Amadei 4, Alfredo Di Nola 2
1Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy
2Department of Chemistry, University of Rome La Sapienza, Rome, Italy
3Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv, Israel
4Dipartimento di Scienze e Tecnologie Chimiche, University of Rome Tor Vergata, Rome, Italy
5Center for Biomolecular Interdisciplinary Studies and Industrial Applications, University of Milano, Milano, Italy

email: Giorgio Colombo (g.colombo@icrm.cnr.it)

*Correspondence to Giorgio Colombo, Istituto di Chimica del Riconoscimento Molecolare, CNR, Via Mario Bianco 9, 20131 Milano, Italy

Funded by: EU community; Grant Number: RTN grant HPRN-CT-2002-00241
Israel Science Foundation (F.I.R.S.T program)

Keywords: core-recognition motif . molecular dynamic simulation . amyloid polypeptide

FULL TEXT

Abstract

The formation of amyloid fibrils is associated with major human diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. Here, we used molecular dynamics simulations to study the initial self-assembly stages of the NH2-NFGAIL-COOH peptide, the core-recognition motif of the type II diabetes associated islet amyloid polypeptide. The simulations were performed using multiple replicas of the monomers in explicit water, in a confined box starting from a random distribution of the peptides at T = 300 K and T = 340 K. At both temperatures the formation of unique clusters was observed after a few nanoseconds. Structural analysis of the clusters clearly suggested the formation of flat ellipsoid-shaped clusters through a preferred locally parallel alignment of the peptides. The unique assembly is facilitated by a preference for an extended conformation of the peptides and by intermolecular aromatic interactions. Taken together, our results may provide a description of the molecular recognition determinants involved in fibril formation, in terms of the atomic detailed structure of nascent aggregates. These observations may yield information on new ways to control this process for either materials development or drug design. Proteins 2005. (c) 2005 Wiley-Liss, Inc.