When calculating the free-energy of ions permeating membrane proteins, an initial decision to make is how many ions needs to be included in the calculation. This decision is usually based on previous knowledge (both experiments and simulations), and on the intuition of the researcher. But intuition might be wrong… And taking the number of ions wrong might render free-energy profiles that are not representative of how the protein actually operates, or it can make extremely inefficient the estimate of robust free-energy profiles. To solve this problem, we decided to develop a simulation protocol that can easily deal with an arbitrary number of ions inside the permeating pore. This was achieved by using Bias-Exchange Metadynamics. The method was compared with more classical Umbrella Sampling simulations, proving that it renders similar free-energy profiles with less computational resources, while at the same time releasing the researcher from choosing the exact number of ions involved in conduction events. In following studies, we used this Bias-Exchange approach to simulate conduction in TRPV ion channels, where the no previous info about the exact number of ions was available.
Domene, C., Barbini, P. & Furini, S. Bias-exchange metadynamics simulations: An efficient strategy for the analysis of conduction and selectivity in ion channels. J. Chem. Theory Comput. 11, 1896–1906 (2015).
Jorgensen, C., Furini, S. & Domene, C. Energetics of Ion Permeation in an Open-Activated TRPV1 Channel. Biophys. J. 111, 1214–1222 (2016).
