Recent NMR experiments have revealed that a single residue mutation W62G on protein hen's-egg white lysozyme can cause a dramatic loss of long-range interactions and protein stability; however, the molecular mechanism for this surprising phenomenon is not completely clear. In this mini-review, we have summarized some of our recent work on the molecular mechanism with large-scale molecular modelling, and also utilized a new wavelet method to analyse the local structural clusters present in both the wild-type and mutant folding trajectories. These extensive MD (Molecular Dynamics) simulations (10+ μs) were performed in 8 M urea, mimicking the experimental condition. Detailed analyses revealed that the Trp62 residue is the key to a co-operative long-range interaction within the wild-type protein: it acts as a bridge between neighbouring basic residues, mainly arginine residues, through π-type hydrogen bonds or π-cation interactions to form an Arg-Trp-Arg ‘sandwich-like’ local structure. The local cluster near Trp62 further extends its interaction to other clusters, such as the one near Trp111, through Arg112, which is involved in such an Arg-Trp-Arg bridging structure, thus achieving the long-range interactions for the wild-type. On the other hand, the mutant does not have this bridging effect and forms much less local clusters or contacts, and therefore results in a much less stable structure. Overall, these findings not only support the general conclusions of the experiment, but also provide a detailed but somewhat different molecular picture of the disruption of the long-range interactions.
Conference Article| November 23 2007
Single-mutation-induced stability loss in protein lysozyme
R. Zhou 1
†Computational Biology Center, IBM Watson Research Center, Deep Computing Institute, Yorktown Heights, NY 10598, U.S.A.
‡Department of Chemistry, Columbia University, New York, NY 10027, U.S.A.
1To whom correspondence should be addressed (email email@example.com)
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L. Ye, Z. Wu, M. Eleftheriou, R. Zhou; Single-mutation-induced stability loss in protein lysozyme. Biochem Soc Trans 1 December 2007; 35 (6): 1551–1557. doi: https://doi.org/10.1042/BST0351551
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