Dynamics of Neurotoxin II Provides Adaptivity of its Functional Sites

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The details of protein internal motions could be of crucial importance to understanding its function. Such a details can't be directly obtained by conventional NMR methods: the set of NMR structures and relaxation order parameters do not provide motional models. One of the viable approaches is the analysis of molecular dynamics trajectories verified by NMR structural and relaxation data sets. The technique was implemented to the peripheral protein Neurotoxin II (NTII). High-quality experimental structures of 13С/15N labeled NTII were used as starting points for a set of MD trajectories covering a total of 7 microseconds. 3JHNHA, 3JHAHB and 3JHBHG coupling constants together with backbone and sidechain 15N-/13C-relaxation rates, heteronuclear NOEs and chemical shifts were back-calculated from MD trajectories and found to be in a good agreement with experimental data. The analysis of MD trajectories revealed a number of highly flexible protein regions with locally correlated motions in the nanosecond time scale. Two of the regions, as was shown previously, provide NTII binding to the environment of the Nicotinic Acetylcholine Receptor (nAChR) and to the receptor itself. Flexibility of protein binding sites could lead to their adaptivity favoring binding to target molecules. In the case of NTII two flexible binding sites of different targeting (membrane binding site and nAChR inhibition site) act successively. High flexibility of the binding site of NTII provides its adaptivity to the specific interaction with the lipid head groups of phosphatidylserine in the environment of nAChR enabling the membrane catalysis mechanism for NTII/nAChR interaction. Then high flexibility and, accordingly, adaptivity of the nAChR inhibition site of NTII plays its role in the final step of the membrane catalysis - high affinity binding of NTII to nAChR.