1.. _fepmf: 2 3Calculating a PMF using the free-energy code 4-------------------------------------------- 5 6The free-energy coupling-parameter approach (see sec. :ref:`fecalc`) 7provides several ways to calculate potentials of mean force. A potential 8of mean force between two atoms can be calculated by connecting them 9with a harmonic potential or a constraint. For this purpose there are 10special potentials that avoid the generation of extra exclusions, 11see sec. :ref:`excl`. When the position of the minimum or the constraint 12length is 1 nm more in state B than in state A, the restraint or 13constraint force is given by :math:`\partial H/\partial \lambda`. The 14distance between the atoms can be changed as a function of 15:math:`\lambda` and time by setting delta-lambda in the :ref:`mdp` file. The 16results should be identical (although not numerically due to the 17different implementations) to the results of the pull code with umbrella 18sampling and constraint pulling. Unlike the pull code, the free energy 19code can also handle atoms that are connected by constraints. 20 21Potentials of mean force can also be calculated using position 22restraints. With position restraints, atoms can be linked to a position 23in space with a harmonic potential (see :ref:`positionrestraint`). 24These positions can be made a function of the coupling parameter 25:math:`\lambda`. The positions for the A and the B states are supplied 26to :ref:`grompp <gmx grompp>` with the ``-r`` and ``-rb`` options, respectively. One could use this 27approach to do targeted MD; note that we do not encourage the use of 28targeted MD for proteins. A protein can be forced from one conformation 29to another by using these conformations as position restraint 30coordinates for state A and B. One can then slowly change 31:math:`\lambda` from 0 to 1. The main drawback of this approach is that 32the conformational freedom of the protein is severely limited by the 33position restraints, independent of the change from state A to B. Also, 34the protein is forced from state A to B in an almost straight line, 35whereas the real pathway might be very different. An example of a more 36fruitful application is a solid system or a liquid confined between 37walls where one wants to measure the force required to change the 38separation between the boundaries or walls. Because the boundaries (or 39walls) already need to be fixed, the position restraints do not limit 40the system in its sampling. 41