In general, to overcome the lack of sampling, one can increase simulation time, enhance sampling by means of special algorithms such as replica exchange MD, or decrease the barrier of the biasing potential. Since the sampling of λ-coordinates is tightly coupled to the sampling of the dihedral angles, we propose to reduce the barriers of the torsion potentials of the side chains in titratable amino acids. Similar strategies have been also adopted before in constant pH MD simulations. 9, Alternatively, increased sampling of side chain rotamer states has been achieved using pH replica exchange methods. However, these methods are computationally more demanding than performing a single MD simulation and also prevent access to the dynamical properties of the system because of jumps between replicas.