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Testing Simplified Proteins Models of the hPin1 WW Domain

Fabio Cecconi ^*, Carlo Guardiani  and Roberto Livi 

^* INFM-CNR Istituto dei Sistemi Complessi, Rome, Italy; Centro Interdipartimentale per lo Studio delle Dinamiche Complesse, Sezione INFN di Firenze, Florence, Italy; and Dipartimento di Fisica Università di Firenze, Centro Interdipartimentale per lo Studio delle Dinamiche Complesse, Sezione INFN di Firenze e INFM, Florence, Italy

Correspondence: Address reprint requests to Dr. Fabio Cecconi, Tel.: 39-06-4993-7452; E-mail: cecconif{at}roma1.infn.it.

The WW domain of the human Pin1 protein for its simple topology and large amount of experimental data is an ideal candidate to assess theoretical approaches to protein folding. The purpose of this work is to compare the reliability of the chemically based Sorenson/Head-Gordon (SHG) model and a standard native centric model in reproducing, through molecular dynamics simulations, some of the well known features of the folding transition of this small domain. Our results show that the G model correctly reproduces the cooperative, two-state, folding mechanism of the WW-domain, while the SHG model predicts a transition occurring in two stages: a collapse, followed by a structural rearrangement. The lack of a cooperative folding in the SHG simulations appears to be related to the nonfunnel shape of the energy landscape featuring a partitioning of the native valley in subbasins corresponding to different chain chiralities. However, the SHG approach remains more reliable in estimating the -values with respect to G-like description. This may suggest that the WW-domain folding process is stirred by energetic and topological factors as well, and it highlights the better suitability of chemically based models in simulating mutations.

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