Open Access Methodology article

The redundancy of NMR restraints can be used to accelerate the unfolding behavior of an SH3 domain during molecular dynamics simulations

Nathalie Duclert-Savatier1, Leandro Martínez2, Michael Nilges1 and Thérèse E Malliavin1*

Author Affiliations

1 Institut Pasteur, CNRS URA 2185, Unité de Bioinformatique Structurale, 25-28 rue du Dr Roux, F-75724 Paris Cedex 15, France

2 Instituto de Física de São Carlos, Universidade de São Paulo. Av. Trabalhador São-carlense 400, 13566-590 São Carlos, SP, Brasil

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BMC Structural Biology 2011, 11:46  doi:10.1186/1472-6807-11-46

Published: 24 November 2011

Abstract

Background

The simulation of protein unfolding usually requires recording long molecular dynamics trajectories. The present work aims to figure out whether NMR restraints data can be used to probe protein conformations in order to accelerate the unfolding simulation. The SH3 domain of nephrocystine (nph SH3) was shown by NMR to be destabilized by point mutations, and was thus chosen to illustrate the proposed method.

Results

The NMR restraints observed on the WT nph SH3 domain were sorted from the least redundant to the most redundant ones. Protein NMR conformations were then calculated with: (i) the set full including all NMR restraints measured on nph SH3, (ii) the set reduced where the least redundant restraints with respect to the set full were removed, (iii) the sets random where randomly picked-up restraints were removed. From each set of conformations, we recorded series of 5-ns MD trajectories. The β barrel architecture of nph SH3 in the trajectories starting from sets (i) and (iii) appears to be stable. On the contrary, on trajectories based on the set (ii), a displacement of the hydrophobic core residues and a variation of the β barrel inner cavity profile were observed. The overall nph SH3 destabilization agrees with previous experimental and simulation observations made on other SH3 domains. The destabilizing effect of mutations was also found to be enhanced by the removal of the least redundant restraints.

Conclusions

We conclude that the NMR restraint redundancy is connected to the instability of the SH3 nph domain. This restraint redundancy generalizes the contact order parameter, which is calculated from the contact map of a folded protein and was shown in the literature to be correlated to the protein folding rate. The relationship between the NMR restraint redundancy and the protein folding is also reminiscent of the previous use of the Gaussian Network Model to predict protein folding parameters.

Keywords:
NMR; protein folding; SH3 domain; molecular dynamics simulation; QUEEN; contact order: Gaussian Network Model