In an alchemical transformation, a part of a molecule can turn into dummy atoms that do not interact with the rest of the system, apart from a few kept covalent interactions.
#Schrodinger maestro free#
More generally, the problem of inadequate sampling can be exacerbated in the case of alchemical (i.e., relative) free energy calculations because the system Hamiltonian is manipulated at intermediate stages to have ?unnatural? potential energy surfaces. Starting the simulations with ?-hydrogen in the trans-configuration will lead to a significantly different estimate of protonation free energy.
If the simulations begin with the ?-hydrogen in the cis-configuration, it will remain in the cis-configuration, and the resulting free energy will be the free energy of protonating the glutamic acid into the cis-conformer, not into a mixture of cis/trans-conformers, as it should be. In a typical molecular force field such as AMBER, these two configurations are separated by a high energetic barrier of around 7 kcal/mol, and in a classical MD simulation, the conversion between the two is all but prohibited. In the protonated form, the ?-hydrogen can be in either cis- or trans- configuration with respect to the carbonyl oxygen. In this case, a dummy atom is changed into the ?-hydrogen, as the deprotonated form of the glutamic acid is morphed into its protonated form. To illustrate (perhaps non-obvious) problems associated with inadequate sampling, one needs only to consider the relatively simple example of the free energy of protonation of a glutamic acid. Poor convergence in the free energy estimate can be one indicator of inadequate sampling however, even when small variances in the free energy are obtained, such results alone do not guarantee adequate sampling. In particular, inadequate sampling can often cause problems, sometimes in non-obvious ways. Although the Desmond distribution includes tools to facilitate the setup, running, and analysis of free energy calculations, proper interpretation of free energy results requires extreme caution.
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