Alchemical free energy simulations for biological complexes: powerful but temperamental …

Abstract

Free energy simulations compare multiple ligand:receptor complexes by "alchemically" transforming one into another, yielding binding free energy differences. Since their introduction in the 1980s, many technical and theoretical obstacles were surmounted, and the method ("MDFE," since molecular dynamics are often used) has matured into a powerful tool. We describe its current status, its effectiveness, and the challenges it faces. MDFE has provided chemical accuracy for many systems but remains expensive, with significant human overhead costs. The bottlenecks have shifted, partly due to increased computer power. To study diverse sets of ligands, force field availability and accuracy can be a major difficulty. Another difficulty is the frequent need to consider multiple states, related to sidechain protonation or buried waters, for example. Sophisticated, automated methods to sample these states are maturing, such as constant pH simulations. Meanwhile, combinations of MDFE and simpler approaches, like continuum dielectric models, can be very effective. As illustrations, we show how, with careful force field parameterization, MDFE accurately predicts binding specificities between complex tetracycline ligands and their targets. We describe substrate binding to the aspartyl-tRNA synthetase enzyme, where many distinct electrostatic states play a role, and a histidine and a Mg(2+) ion act as coupled switches that help enforce a strict preference for the aspartate substrate, relative to several analogs. Overall, MDFE has achieved a predictive status, where novel ligands can be studied and molecular recognition elucidated in depth. It should play an increasing role in the analysis of complex cellular processes and biomolecular engineering.

Mechanism of activation of elongation factor Tu by ribosome: Catalytic histidine activates GTP by protonation

“…The MDFE method follows the horizontal legs of the cycle. Protonated histidine is reversibly transformed into its deprotonated form during a series of MD simulations and the corresponding work is derived from a thermodynamic integration formula (Simonson 2001;Aleksandrov et al 2010). For the lower leg of the thermodynamic cycle, we simulated methyl-imidazole in solution, which served as the reference molecule, whereas for the upper leg we simulated a portion of the ribosome complex.…”

“…The uncertainty was calculated as the standard deviation of the individual runs obtained in each direction (Aleksandrov et al 2010). This extended simulation length was necessary to correctly sample the important degrees of freedom and to obtain a low statistical uncertainty.…”

MM-GB(PB)SA Calculations of Protein-Ligand Binding Free Energies

“…The lack of a consistent optimum dielectric constant for MM-PBSA calculations has been noted www.intechopen.com by other workers (see for e.g. (Aleksandrov et al 2010)), although generally a value ε in =4 often gives satisfactory results (Aleksandrov et al, 2010;Archontis et al, 2001;Thompson et al, 2006). As a final note, MM-GB(PB)SA calculations require some degree of user expertise and planning, from the initial set-up and analysis of the MD simulations through to the binding free energy calculations themselves.…”

Prediction of Binding Free Energy Calculation Using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) Method in Drug Discovery: A Short Review

“…In a recent MM-PBSA study, researchers suggested that the use of ε in = 4 for a highly charged protein-ligand binding interface, ε in = 2 for a moderately charged binding interface and ε in = 1 for a hydrophobic binding interface may improve ligand ranking [16] . The lack of a consistent optimum dielectric constant for MM-PBSA calculations has been noted by other [20] , although generally a value ε in = 4 often gives satisfactory results [20][21][22] . Finally, MM-PBSA calculations require some degree of user expertise and planning, from the initial set-up and analysis of the MD simulations through to the binding free energy calculations.…”