Free%20Energy%20Calculations%20and%20Ligand%20Binding

Free%20Energy%20Calculations%20and%20Ligand%20Binding -...

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Unformatted text preview: Advances in Protein Chemistry (2003), 66: 123-158 Free Energy Calculations and Ligand Binding Bjørn O. Brandsdal, Fredrik Österberg, Martin Almlöf, Isabella Feierberg, Victor B. Luzhkov and Johan Åqvist * Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-75124 Uppsala, Sweeden, *Corresponding author : E-mail: aqvist@xray.bmc.uu.se Phone: +46 18 471 41 09 Fax: +46 18 53 69 71 2 Contents I. Introduction...........................................................................................................3 II. Free Energy Perturbation and Thermodynamic Integration. ................................6 III. Extrapolation of Free Energies. ..........................................................................17 IV. Linear Interaction Energy Approaches...............................................................21 V. MM-PBSA..........................................................................................................31 VI. PROFEC. ............................................................................................................35 VII. λ-Dynamics and Chemical MC/MD...................................................................37 VIII. Concluding Remarks...........................................................................................41 IX. Acknowledgements.............................................................................................44 References....................................................................................................................45 Figure Legends.............................................................................................................49 Figures..........................................................................................................................52 3 I. Introduction The ability of proteins to bind to one another and to different ligands in a highly specific manner is an important feature of many biological processes. The characterization of the structure and the energetics of molecular complexes is thus a key factor for understanding biological functions and the energetics often provides the most important and useful link between structure and function of biomolecular systems. Furthermore, the prediction and design of ligands that can reversibly bind to pharmaceutical targets (enzyme inhibitors, receptor agonists and antagonists etc.) is at the heart of structure-based drug design. To be able to predict the strength of noncovalent associations, as well as the structures of molecular complexes, has therefore been an important objective in computational chemistry. A number of different types of computational approaches have been developed over the years for predicting binding constants. These range from purely empirical or statistical ones, such as QSAR, to more or less rigorous methods based on evaluation of the actual physical energies involved in the binding process. When it comes to of the actual physical energies involved in the binding process....
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This note was uploaded on 12/13/2010 for the course GENETIK 12 taught by Professor Atillabasar during the Spring '10 term at Istanbul Technical University.

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Free%20Energy%20Calculations%20and%20Ligand%20Binding -...

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