In molecular mechanics, several ways exist to define the environment surrounding a molecule or molecules of interest. A system can be simulated in vacuum (termed a gas-phase simulation) with no surrounding environment, but this is usually undesirable because it introduces artifacts in the molecular geometry, especially in charged molecules. Surface charges that would ordinarily interact with solvent molecules instead interact with each other, producing molecular conformations that are unlikely to be present in any other environment. The best way to solvate a system is to place explicit water molecules in the simulation box with the molecules of interest and treat the water molecules as interacting particles like those in the molecule. A variety of water models exist with increasing levels of complexity, representing water as a simple hard sphere (a united-atom model), as three separate particles with fixed bond angles, or even as four or five separate interaction centers to account for unpaired electrons on the oxygen atom. As water models grow more complex, related simulations grow more computationally intensive. A compromise method has been found in implicit solvation, which replaces the explicitly represented water molecules with a mathematical expression that reproduces the average behavior of water molecules (or other solvents such as lipids). This method is useful to prevent artifacts that arise from vacuum simulations and reproduces bulk solvent properties well, but cannot reproduce situations in which individual water molecules have interesting interactions with the molecules under study.

The main use of molecular mechanics is in the field of molecular dynamics. This uses the force field to calculate the forces acting on each particle and a suitable integrator to model the dynamics of the particles and predict trajectories. Given enough sampling and subject to the ergodic hypothesis, molecular dynamics trajectories can be used to estimate thermodynamic parameters of a system or probe kinetic properties, such as reaction rates and mechanisms.

Another application of molecular mechanics is energy minimization, whereby the force field is used as an optimization criterion. This method uses an appropriate algorithm (e.g. steepest descent) to find the molecular structure of a local energy minimum. These minima correspond to stable conformers of the molecule (in the chosen force field) and molecular motion can be modelled as vibrations around and interconversions between these stable conformers. It is thus common to find local energy minimization methods combined with global energy optimization, to find the global energy minimum (and other low energy states). At finite temperature, the molecule spends most of its time in these low-lying states, which thus dominate the molecular properties. Global optimization can be accomplished using simulated annealing, the Metropolis algorithm and other Monte Carlo methods, or using different deterministic methods of discrete or continuous optimization. While the force field represents only the enthalpic component of free energy (and only this component is included during energy minimization), it is possible to include the entropic component through the use of additional methods, such as normal mode analysis.

Molecular mechanics potential energy functions have been used to calculate binding constants, protein folding kinetics, protonation equilibria, active site coordinates, and to design binding sites

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Nancy Ella

Managing Editor

Drug Designing: Open Access