Computational Drug Discovery and Design

couple-lambda0andcouple-lambda1define the state of

the intermolecular interactions atλvalues of zero and one,

respectively; in this case we are defining that at lambda zero

both coulombic and vdW interactions are on, while they are off

at lambda one (i.e., the ligand is decoupled while going from

lambda zero to one).bonded-lambdasdefines the vector of

λrestrvalues, since the restraints can be applied as additional

bonded terms between different molecules, as shown inNote

6. This vector can be omitted when decoupling the ligand from

solution, since for that leg of the cycle the contribution of the

restraints can be obtained analytically.coul-lambdasand

vdw-lambdas define instead the lambda vectors for the

decoupling of the coulombic and Lennard–Jones interactions.

In this example, there are seven states to be simulated, each

defined by a column of the vectors above.init-lambda-

stateis then used in the mdp file in order to choose which

column is being simulated; for instance, init-lambda-

state¼ 0 means that the index 0 of the lambda arrays is

simulated (λrestr¼0.0,λcoul¼0.0,λvdw¼0.0), whileinit-

lambda-state¼ 3 means that index 3 of the arrays is

simulated (λrestr¼1.0,λcoul¼0.5,λvdw¼0.0). Additionally,

thecouple-intramolflag can be used to decide whether the

ligand should be decoupled or annihilated.

2. In Gromacs, the Lennard–Jones soft-core potential by Beutler
   et al. [55] is implemented and can be used by specifying the
   following in the mdp file.

sc-alpha = 0.5

sc-power = 1

sc-sigma = 0.3

These three parameters define the soft-cored

Lennard–Jones function [55]. In particular, the alpha parame-

ter needs to be larger than zero for the LJ interactions to be

soft-cored. An sc-alpha of 0.5, sc-power of 1, and

sc-sigmaof 0.3 are typically used values [33, 54, 56, 69, 93].

3. A soft-core potential for the coulombic interactions can be
   activated in Gromacs with the mdp optionsc-coul. However,
   for equilibrium ABFE calculations, it is not clear whether
   performing the coulombic and vdW transformations simulta-
   neously would result in much better efficiency as compared to
   performing the transformation separately. In fact, since the
   charge decoupling process typically shows good overlap
   between windows and smoothh∂U/∂λi,few windows are
   usually necessary [61, 93, 94].


4. One might think that in order to keep the neutrality of the box
   it could also be possible to (de)couple an ion from solution

224 Matteo Aldeghi et al.