Native protein fluctuations: the conformational-motion temperature and the inverse correlation of protein flexibility with protein stability.

We study the fluctuations of native proteins by exact enumeration using the HP lattice model. The model fluctuations increase with temperature. We observe a low-temperature point, below which large fluctuations are frozen out. This prediction is consistent with the observation by Tilton et al. [R. F. Tilton, Jr., J. C. Dewan, and G. A. Petsko, Biochemistry 31, 2469 (1992)], that the thermal motions of ribonuclease A increase sharply above about 200 K. We also explore protein "flexibility" as defined by Debye-Waller-like factors and solvent accessibilities of core residues to hydrogen exchange. We find that proteins having greater stability tend to have fewer large fluctuations, and hence lower flexibilities. If flexibility is necessary for enzyme catalysis, this could explain why proteins from thermophilic organisms, which are exceptionally stable, may be catalytically inactive at normal temperatures.