We study the nature of biomolecular binding. We found that in general there exists several thermodynamic phases: a native binding phase, a non-native phase, and a glass or local trapping phase. The quantitative optimal criterion for the binding specificity is found to be the maximization of the ratio of the binding transition temperature versus the trapping transition temperature, or equivalently the ratio of the energy gap of binding between the native state and the average non-native states versus the dispersion or variance of the non-native states. This leads to a funneled binding energy landscape.

The steadily increasing number of high-resolution human immunodeficiency virus (HIV) 1 protease complexes has been the impetus for the elaboration of knowledge-based mean field ligand-protein interaction potentials. These potentials have been linked with the hydrophobicity and conformational entropy scales developed originally to explain protein folding and stability. Empirical free energy calculations of a diverse set of HIV-1 protease crystallographic complexes have enabled a detailed analysis of binding thermodynamics. The thermodynamic consequences of conformational changes that HIV-1 protease undergoes upon binding to all inhibitors, and a substantial concomitant loss of conformational entropy by the part of HIV-1 protease that forms the ligand-protein interface, have been examined. The quantitative breakdown of the entropy-driven changes occurring during ligand-protein association, such as the hydrophobic contribution, the conformational entropy term and the entropy loss due to a reduction of rotational and translationsal degrees of freedom, of a system composed of ligand, protein and crystallographic water molecules at the ligand-protein interface has been carried out The proposed approach provides reasonable estimates of distinctions in binding affinity and gives an insight into the nature of enthalpy-entropy compensation factors detected in the binding process.

Hsp90 is a molecular chaperone essential for protein folding and activation in normal homeostasis and stress response. ATP binding and hydrolysis facilitate Hsp90 conformational changes required for client activation. Hsp90 plays an important role in disease states, particularly in cancer, where chaperoning of the mutated and overexpressed oncoproteins is important for function. Recent studies have illuminated mechanisms related to the chaperone function. However, an atomic resolution view of Hsp90 conformational dynamics, determined by the presence of different binding partners, is critical to define communication pathways between remote residues in different domains intimately affecting the chaperone cycle. Here, we present a computational analysis of signal propagation and long-range communication pathways in Hsp90. We carried out molecular dynamics simulations of the full-length Hsp90 dimer, combined with essential dynamics, correlation analysis, and a signal propagation model. All-atom MD simulations with timescales of 70 ns have been performed for complexes with the natural substrates ATP and ADP and for the unliganded dimer. We elucidate the mechanisms of signal propagation and determine “hot spots” involved in interdomain communication pathways from the nucleotide-binding site to the C-terminal domain interface. A comprehensive computational analysis of the Hsp90 communication pathways and dynamics at atomic resolution has revealed the role of the nucleotide in effecting conformational changes, elucidating the mechanisms of signal propagation. Functionally important residues and secondary structure elements emerge as effective mediators of communication between the nucleotide-binding site and the C-terminal interface. Furthermore, we show that specific interdomain signal propagation pathways may be activated as a function of the ligand. Our results support a “conformational selection model” of the Hsp90 mechanism, whereby the protein may exist in a dynamic equilibrium between different conformational states available on the energy landscape and binding of a specific partner can bias the equilibrium toward functionally relevant complexes. Dynamic processes underlie the functions of all proteins. Hence, to understand, control, and design protein functions in the cell, we need to unravel the basic principles of protein dynamics. This is fundamental in studying the mechanisms of a specific class of proteins known as molecular chaperones, which oversee the correct conformational maturation of other proteins. In particular, molecular chaperones of the stress response machinery have become the focus of intense research, because their upregulation is responsible for the ability of tumor cells to cope with unfavorable environments. This is largely centered on the expression and function of the molecular chaperone Hsp90, which has provided an attractive target for therapeutic intervention in cancer. Experiments have shown that the chaperone functions through a nucleotide-directed conformational cycle. Here, we show that it is possible to identify the effects of nucleotide-related chemical differences on functionally relevant motions at the atomic level of resolution. The protein may fluctuate at equilibrium among different available dynamic states, and binding of a specific partner may shift the equilibrium toward the thermodynamically most stable complexes. These results provide us with important mechanistic insight for the identification of new regulatory sites and the design of possible new drugs.