Allosteric changes in protein structure computed by a simple mechanical model: hemoglobin T/ R2 transition

Information on protein dynamics has been usually inferred from spectro-scopic studies of parts of the proteins, or indirectly from the comparison of the conformations assumed in the presence of different substrates or ligands. While molecular simulations also provide information on protein dynamics, they usually suffer from incomplete sampling of conformational space, and become prohibitively expensive when exploring the collective dynamics of large macromolecular structures. Here, we explore the dynamics of a well-studied allosteric protein, hemoglobin (Hb), to show that a simple mechanical model based on Gaussian fluctuations of resi-dues can efficiently predict the transition between the tense (T, un-liganded) and relaxed (R or R2, O2 or CO-bound) forms of Hb. The passage from T into R2 is shown to be favored by the global mode of motion, which, in turn is driven by entropic effects. The major difference between the dynamics of the T and R2 forms is the loss of the hinge-bending role of a1 –b2 (or a2 –b1) interfacial residues at aPhe36-His45 and bThr87-Asn102 in the R2 form, which implies a decreased cooperativity in the higher affinity (R2) form of Hb, consistent with many experimental studies. The involvement of the proximal histidine bHis92 in this hinge region suggests that the allosteric propagation of the local structural changes (induced upon O2 binding) into global ones occur via hinge regions. This is the first demonstration that there is an intrinsic tendency of Hb to undergo T! R2 transition, induced by purely elastic forces of entropic origin that are uniquely defined for the particular contact top-ology of the T form