MacroModel Reference Manual - ISP

Appendix G: MINTA Backgroundalone cannot presently provide converged free-energy simulation results. Conformational analysisis therefore a prerequisite for any free-energy calculation involving highly flexibledocking (especially if three-dimensional structural data are not available), whether it is basedon MD or MMC simulation, or a direct approach such as MINTA.Before starting a detailed discussion of free-energy simulation techniques and the place forMINTA among them, let us provide recent literature references to the state-of-the-art of calculatingprotein-ligand binding affinities. Reviews include Kollman (1993), Ajay and Murcko(1995), Gilson et al. (1997), Lamb and Jorgensen (1997), and Babine and Bender (1997).G.2 The Thermodynamic CycleThe thermodynamic cycle is based on the fact that free energy is a state function. For examplewe want to calculate the binding free-energy difference between two ligands with respect to thesame macromolecular host in solution. The corresponding thermodynamic cycle can be writtenas follows:H(s) + L A (s)∆G 1HL A (s)∆G 3∆G 2∆G 4H(s) + L B (s)HL B (s)∆∆G AB = ∆G 1 – ∆G 2 = ∆G 3 – ∆G 4(1)The natural, chemical path would be along the horizontal arrows (∆G 1 -∆G 2 ) corresponding tothe actual chemical complex formation. However, the associated simulations are unfortunatelysubject to excessive statistical error rendering this approach extremely unstable and virtuallyuseless. On the other hand, the counterintuitive path along the vertical arrows (∆G 3 -∆G 4 )isnon-chemical, nonetheless, it is well suited for simulations. The computational procedure oftenreferred to as computational alchemy involves “mutating” L A into L B once in pure solvent andthen again in the binding cavity of the protein host H. The numerical values of ∆G 3 and ∆G 4can be obtained by many different ways based on different levels of approximation, which willbe discussed below.Equation (1) is used to calculate relative binding free energies. The thermodynamic cycle,however, can be used to estimate absolute free energies as well. This procedure is termeddouble annihilation and the corresponding thermodynamic cycle can be written as a “balance”equation, as in Equation (2).228MacroModel 9.7 Reference Manual