Computational Drug Discovery and Design

Considerations about the quality of the starting structure and

the modeling of the system’s chemistry are important too. For

instance, the ligand might have multiple protonation and tautomer

states in solution, without a single one being necessarily largely

dominant. In addition, the solvent and the protein represent two

very different environments, so that pKashifts are possible and the

protonation states of the ligand or protein residues may change

between the unbound and bound states. Currently, this is not

inherently captured by typical simulations. These complications

might thus require multiple calculations or more advanced proto-

cols that correctly take into account the contributions arising from

the presence of multiple molecular species in equilibrium. Further-

more, the suitability of the force field for the molecules studied can

clearly have important effects on the accuracy of the calculated

affinities. Given the vast chemical space of small drug-like mole-

cules, the transferability of certain parameters, such as those for the

torsions, can be problematic and may result in inaccurate energies

and relative conformational populations. This, in turn, may affect

the binding free energy results in ways that are hard to foresee.

Small molecule parameters can be refined, for instance, by targeting

quantum mechanical energies [8, 51] but it is up to the user to

decide how much human and computational effort to invest in

order to validate the quality of the parameters.

5 Notes

In these Notes we describe how specific steps can be carried out in

Gromacs 2016. It is however recommended to also refer to the

Gromacs manual for additional details, in particular considering

possible changes/developments in future versions of the software.

1. In Gromacs, the fictitious alchemical path depicted in Fig. 3
   and pertaining to the simulations of the protein–ligand com-
   plex could be implemented via options in the mdp file as
   follows.

free-energy = yes

couple-moltype = ligand

couple-lambda0 = vdw-q

couple-lambda1 = none

bonded-lambdas = 0.0 0.5 1.0 1.0 1.0 1.0 1.0

coul-lambdas = 0.0 0.0 0.0 0.5 1.0 1.0 1.0

vdw-lambdas = 0.0 0.0 0.0 0.0 0.0 0.5 1.0

Thefree-energyflag tells the code we are performing

free energy calculations;couple-moltypedefines the mole-

cule type, as defined in the topology, that is to be (de)coupled.

Absolute Alchemical Free Energy 223