Application of the free energy calculations to study drug-enzyme and drug-DNA complexes

Applications of two free energy calculation approaches are presented to study drug-biomolecule complexes. The first method, the free energy perturbation (FEP) method and molecular dynamics simulations has been applied to study the JG-365 inhibitor bound to the HIV-aspartic protease. The FEP method has been applied to predict the consequence of replacing each of the seven peptide bonds in the JG-365 by trans-ethylene or fluoroethylene units. The necessary initial conformations of the inhibitor for "in water" perturbations have been found using neural network clustering approach applied to the long molecular dynamics trajectory of the inhibitor in water solution. The second method is applied to study binding free energies of some DNA-drug complexes and is based on analysis of long molecular dynamics trajectories by continuum solvent approach (MM/PBSA).