Asymmetric folding pathways and transient misfolding in a coarse-grained model of proteins

¹ School of Physics, University of Edinburgh - JCMB Kings Buildings, Edinburgh EH9 3JZ, UK, EU
² Department of Chemistry, University of Cambridge - Lensfield Road, Cambridge CB2 1EW, UK, EU
³ Institut für Theoretische Physik, Universität zu Köln - Zülpicher Str. 77, 50937 Köln, Germany, EU

^a katrin.wolff@ed.ac.uk

Received: 9 February 2011
Accepted: 11 April 2011

Abstract

Coarse-grained approaches to study the protein folding process provide the possibility to explore timescales longer than those accessible to all-atom models and thus provide access, albeit in less detail, to larger regions of the conformational space. Here, we investigate the behaviour of a coarse-grained model whose two primary characteristics are a tube-like geometry to describe the self-avoidance effects of the polypeptide chain, and an energy function based on a one-dimensional structural representation that specifies the sequence's connectivity in a given conformation. Such an energy function, rather than favouring the formation of specific native pairwise contacts, promotes the establishment of a specific target connectivity for each amino acid. We illustrate the use of this model by showing that it enables to follow the complete process of folding and to efficiently determine the free energy landscapes of two small α-helical proteins, the villin headpiece domain and the ubiquitin associated domain, providing results that closely resemble those found in extensive molecular dynamics studies. These results support the idea that the use of coarse-grained models that capture the self-avoidance and the connectivity of a polypeptide chain represents a promising approach for obtaining effective descriptions of many aspects of the behaviour of proteins.