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      MM-PBSA Captures Key Role of Intercalating Water Molecules at a Protein−Protein Interface


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          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.

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          Revisiting free energy calculations: a theoretical connection to MM/PBSA and direct calculation of the association free energy.

          The prediction of absolute ligand-receptor binding affinities is essential in a wide range of biophysical queries, from the study of protein-protein interactions to structure-based drug design. End-point free energy methods, such as the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) model, have received much attention and widespread application in recent literature. These methods benefit from computational efficiency as only the initial and final states of the system are evaluated, yet there remains a need for strengthening their theoretical foundation. Here a clear connection between statistical thermodynamics and end-point free energy models is presented. The importance of the association free energy, arising from one molecule's loss of translational and rotational freedom from the standard state concentration, is addressed. A novel method for calculating this quantity directly from a molecular dynamics simulation is described. The challenges of accounting for changes in the protein conformation and its fluctuations from separate simulations are discussed. A simple first-order approximation of the configuration integral is presented to lay the groundwork for future efforts. This model has been applied to FKBP12, a small immunophilin that has been widely studied in the drug industry for its potential immunosuppressive and neuroregenerative effects.
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            Assessing implicit models for nonpolar mean solvation forces: the importance of dispersion and volume terms.

            Continuum solvation models provide appealing alternatives to explicit solvent methods because of their ability to reproduce solvation effects while alleviating the need for expensive sampling. Our previous work has demonstrated that Poisson-Boltzmann methods are capable of faithfully reproducing polar explicit solvent forces for dilute protein systems; however, the popular solvent-accessible surface area model was shown to be incapable of accurately describing nonpolar solvation forces at atomic-length scales. Therefore, alternate continuum methods are needed to reproduce nonpolar interactions at the atomic scale. In the present work, we address this issue by supplementing the solvent-accessible surface area model with additional volume and dispersion integral terms suggested by scaled particle models and Weeks-Chandler-Andersen theory, respectively. This more complete nonpolar implicit solvent model shows very good agreement with explicit solvent results and suggests that, although often overlooked, the inclusion of appropriate dispersion and volume terms are essential for an accurate implicit solvent description of atomic-scale nonpolar forces.
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              The entropic cost of bound water in crystals and biomolecules.

              J Dunitz (1994)

                Author and article information

                J Chem Theory Comput
                Journal of Chemical Theory and Computation
                American Chemical Society
                22 January 2009
                10 February 2009
                : 5
                : 2
                : 422-429
                [1]Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Department of Pharmacology, and Howard Hughes Medical Institute, University of California at San Diego, La Jolla, California 92093-0365
                Author notes
                [* ] Corresponding author phone: (858)822-1469; fax: (858)534-4974; e-mail: swong@ 123456mccammon.ucsd.edu (S.W.), ramaro@ 123456mccammon.ucsd.edu (R.E.A.). Corresponding author address: Department of Chemistry & Biochemistry, University of California San Diego, 9500 Gilman Drive, Mail Code 0365, La Jolla, CA 92093-0365.

                These authors contributed equally to this work.


                Department of Chemistry and Biochemistry and Center for Theoretical Biological Physics.


                Department of Pharmacology.


                Howard Hughes Medical Institute.

                Copyright © 2009 American Chemical Society

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                National Institutes of Health, United States
                Custom metadata

                Computational chemistry & Modeling
                Computational chemistry & Modeling


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