Catalysis by entropic guidance from enzymes.

Certain features underlying enzymatic catalysis, such as energetic stabilization from binding interactions or proximity and orientation of chemical groups, are evident in the equilibrium-averaged structure of an enzymatic complex determined by crystallography or NMR. Transient features are not apparent from an average structure. Here, we report on a catalytically relevant property of an enzymatic complex revealed by thermal fluctuations from a molecular dynamics study. The conformational fluctuations of the cofactor NADH are altered by binding the enzyme lactate dehydrogenase (LDH) compared to those of free NADH; thermal motions give rise to structures similar to that of the putative transition state. The alteration is stereospecific, in agreement with measured changes in vibrational spectra, and leads to an understanding of the correlation, established some time ago by crystallography and NMR, between the nicotinamide glycosidic bond torsion angle (anti/syn) and the stereospecificity of hydride transfer. These results suggest that one catalytic role of the enzyme is to funnel the population of NADH conformers to the transition state and reduce the entropic barrier to activation. The specific motions in an enzyme complex that might function to enhance transition state formation are described.