Allostery can occur by way of subtle cooperation among protein residues (e.g., amino acids) even in the absence of large conformational shifts. Dynamical network analysis has been used to model this cooperation, helping to computationally explain how binding to an allosteric site can impact the behavior of a primary site many ångstroms away. Traditionally, computational efforts have focused on the most optimal path of correlated motions leading from the allosteric to the primary active site. We present a program called Weighted Implementation of Suboptimal Paths (WISP) capable of rapidly identifying additional suboptimal pathways that may also play important roles in the transmission of allosteric signals. Aside from providing signal redundancy, suboptimal paths traverse residues that, if disrupted through pharmacological or mutational means, could modulate the allosteric regulation of important drug targets. To demonstrate the utility of our program, we present a case study describing the allostery of HisH-HisF, an amidotransferase from T. maritima thermotiga. WISP and its VMD-based graphical user interface (GUI) can be downloaded from http://nbcr.ucsd.edu/wisp.

The calculation of protein interaction energetics is of fundamental interest, yet accurate quantities are difficult to obtain due to the complex and dynamic nature of protein interfaces. This is further complicated by the presence of water molecules, which can exhibit transient interactions of variable duration and strength with the protein surface. The T-cell receptor (TCR) and its staphylococcal enterotoxin 3 (SEC3) binding partner are well-characterized examples of a protein-protein interaction system exhibiting interfacial plasticity, cooperativity, and additivity among mutants. Specifically engineered mutants induce intercalating interfacial water molecules, which subsequently enhance protein-protein binding affinity. In this work, we perform a set of molecular mechanics (MM) Poisson-Boltzmann (PB) surface area (SA) calculations on the wild type and two mutant TCR-SEC3 systems and show that the method is able to discriminate between weak and strong binders only when key explicit water molecules are included in the analysis. The results presented here point to the promise of MM-PBSA toward rationalizing molecular recognition at protein-protein interfaces, while establishing a general approach to handle explicit interfacial water molecules in such calculations.