Because of how potentials are defined, what gradual removal means can be somewhat subtle. When removing atoms from a system, the atoms should be removed gradually. Guideline 1: Always use soft-core potentials while decoupling or annihilating Lennard-Jones interactions We believe that a basic list of rules and guidelines should be followed in any calculation that involves insertion or deletion: By insertion and deletion, we mean decoupling or annihilation (see Decoupling and annihilation for definitions) of the interactions of the atoms in question. Guidelines for free energy calculation pathwaysĪlchemical free energies almost involve some insertion or deletion of atoms - both in hydration free energy calculations, and in absolute and relative binding free energy calculations. Version control your scripts (using SVN or Git) so you can go back check this record more easily. Not only can scripts help mistakes, but when they do have bugs, the script itself provides a permanent record of exactly what you did. Periodically validate the results of automated scripts, especially when you change them. Instead, when possible, automate simulation preparation tasks so that they do not need to be done manually. Additionally, if your mistake is a result of mistyping something or similar, you may end up with no record of what you did wrong. It is extremely easy to make a mistake that affects the entire subsequent set of simulations. If you manually set up your systems for simulation, we would urge you not to. Guidelines for setting up your system files Guideline 1: Automate when possible Often, additional complications make it harder to track down problems when considering binding free energy calculations. Solvation free energies provide a basic starting point for considering a number of the key issues, and are used frequently here because of this and because of their simplicity. While free energy calculations may be done for many different situations, here we focus on best practices for binding and solvation free energy calculations. A large part of the following discussion will discuss exactly how to construct useful and efficient pathways connecting the end states. Methods which are in principle correct may not always be practical or useful. Some pathways may be more efficient than others (sometimes by many orders of magnitude). Only after free energy estimates have converged can the underlying parameters and physical assumptions really be tested.įree energy is a function of state, so there are many possible choices of pathway for a thermodynamic cycle connecting the same two endpoints. Without convergence, agreement with experiment may be due only to fortuitous cancellation of error. The goal is to obtain that free energy with as little statistical error as possible - and not necessarily to match experiment. Given this particular set of parameters and physical assumptionstarting point, there exists a single right answer for a free energy calculation.
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