Protein-protein binding usually involves structural changes that may extend beyond the rearrangements on a local scale, and cannot be explained by a classical lock-and-key mechanism. Several models have been advanced to explain the flexible binding of proteins such as the induced fit mechanism where the ligand is postulated to induce a conformational change at the interaction site upon binding, or the preexisting equilibrium hypothesis that assumes that protein samples an ensemble of conformations at equilibrium conditions and that the ligand binds selectively to an active conformation. We explored the equilibrium motions of proteins that exhibit relatively large (nonlocal) conformational changes upon protein binding using the Gaussian network model and the anisotropic network model of protein dynamics. For four complexes, LIR-1͞HLA-A2, Actin͞DNase I, CDK2͞cyclin, and CDK6͞ p16 INK4a , the motions calculated for the monomer exhibiting the largest conformational change, in its unbound (free) form, correlate with the experimentally observed structural changes upon binding. This study emphasizes the preexisting equilibrium͞con-formational selection as a mechanism for protein-protein interaction and lends support the concept that proteins, in their native conformation, are predisposed to undergo conformational fluctuations that are relevant to, or even required for, their biological functions.elastic network models ͉ induced fit ͉ lock-and-key mechanism ͉ preexisting equilibrium ͉ protein-protein interactions P rotein-protein interactions underlie the execution and control of cellular activities. Understanding the mechanisms by which protein recognition and interactions occur is a major task both for experimental and computational biology. Several models have been suggested to describe the mechanisms of interactions of proteins, starting from the ''lock-and-key'' model proposed by Emil Fisher (1). While this model insightfully emphasizes the importance of shape complementarity between the two structures, the proteins in their bound form exhibit structural changes with respect to their unbound form. The conformational changes associated with protein-protein interactions vary from local changes in side chains rotameric states to global changes in structure such as collective domain movements (2, 3). The ''induced fit'' model (4) has been introduced to account for this type of plasticity of proteins, as opposed to rigid-docking inherent in the lock-and-key model. The induced fit model suggests that substrate binding induces a change in the 3D structure of its receptor. A geometric fit is thus ensured only after the structural rearrangements of the proteins induced by their recognition͞interaction.Betts and Sternberg (5) analyzed the conformational changes that accompany binding for a set 39 complexes, predominantly enzyme inhibitors; this set of complexes show minor to moderate conformational change. They concluded that (at least for enzyme inhibitors) protein-protein recognition occurs by the mechanism of induced fit....

In recent years, there has been a surge in the number of studies exploring the relationship between proteins' equilibrium dynamics and structural changes involved in function. An emerging concept, supported by both theory and experiments, is that under native state conditions proteins have an intrinsic ability to sample conformations that meet functional requirements. A typical example is the ability of enzymes to sample open and closed forms, irrespective of substrate, succeeded by the stabilization of one form (usually closed) upon substrate binding. This ability is structure-encoded, and plays a key role in facilitating allosteric regulation, which suggests complementing the sequence-encodes-structure paradigm of protein science by structure-encodes-dynamics-encodes-function. The emerging connection implies an evolutionary role in selecting/conserving structures based on their ability to achieve functional dynamics, and in turn, selecting sequences that fold into such 'apt' structures.

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Pairwise interaction models to recognize native folds are designed and analyzed. Different sets of parameters are considered but the focus was on 20 x 20 contact matrices. Simultaneous solution of inequalities and minimization of the variance of the energy find matrices that recognize exactly the native folds of 572 sequences and structures from the protein data bank (PDB). The set includes many homologous pairs, which present a difficult recognition problem. Significant recognition ability is recovered with a small number of parameters (e.g., the H/P model). However, full recognition requires a complete set of amino acids. In addition to structures from the PDB, a folding program (MONSSTER) was used to generate decoy structures for 75 proteins. It is impossible to recognize all the native structures of the extended set by contact potentials. We therefore searched for a new functional form. An energy function U, which is based on a sum of general pairwise interactions limited to a resolution of 1 angstrom, is considered. This set was infeasible too. We therefore conjecture that it is not possible to find a folding potential, resolved to 1 angstrom, which is a sum of pair interactions.

The conformational equilibrium of a blocked valine peptide in water and aqueous urea solution is studied using molecular dynamics simulations. Pair correlation functions indicate enhanced concentration of urea near the peptide. Stronger hydrogen bonding of urea-peptide compared to water-peptide is observed with preference for helical conformation. The potential of mean force, computed using umbrella sampling, shows only small differences between urea and water solvation that are difficult to quantify. The changes in solvent structure around the peptide are explained by favorable electrostatic interactions (hydrogen bonds) of urea with the peptide backbone. There is no evidence for significant changes in hydrophobic interactions in the two conformations of the peptide in urea solution. Our simulations suggest that urea denatures proteins by preferentially forming hydrogen bonds to the peptide backbone, reducing the barrier for exposing protein residues to the solvent, and reaching the unfolded state.