Single-mutation-induced stability loss in protein lysozyme.
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+ micros) were performed in 8 M urea, mimicking the experimental condition. Detailed analyses revealed that the Trp(62) 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 pi-type hydrogen bonds or pi-cation interactions to form an Arg-Trp-Arg 'sandwich-like' local structure. The local cluster near Trp(62) further extends its interaction to other clusters, such as the one near Trp(111), through Arg(112), 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.
Ye
L
L
Department of Computer Science, Zhejiang University, Hangzhou 310027, People's Republic of China.
Wu
Z
Z
Eleftheriou
M
M
Zhou
R
R
D000818:Animals; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics*; D017354:Point Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D013997:Time Factors; D014508:Urea / Q000737:chemistry
D014508:Urea; D009113:Muramidase