M.Ø. Jensen; V. Jogini; M. P. Eastwood and D.E. Shaw. J.Gen. Physiol, 141: 619-632 (2013)
Contributed by Ben Corry
There has been much discussion in these pages about papers assessing the accuracy of classical molecular dynamics in reproducing structural aspects of proteins, but less about whether such simulations can be used to understand physiological processes. Many such processes take place over time scales of ms to s and simulating them directly has long been beyond the scope of atomistic methods. But, the situation is rapidly changing with advances in computer hardware and software. One example of an important physiological process close to my heart is the conduction of ions through trans-membrane channels which underlies electrical signalling in nerve cells and takes place on a ms time scale. I am sure that many of us working in the field have thought that direct atomistic simulations have the potential to elucidate the physical mechanisms underlying this process, and have wondered how accurately such simulations could reproduce this phenomena. Yet again, D.E. Shaw Research provide us with an answer.
Making use of extensive computational resources and more than 1ms of simulation time, Jensen et al1 measure the ionic current passing through a voltage gated potassium channel and the simpler gramicidin A channel under a range of voltages, allowing for a direct comparison to one of the most fundamental experimentally measureable properties. Sadly, the results are disappointing. Currents are about 40 times less and 300 times less than equivalent (highly accurate) experimental measurements in the potassium channel and gramicidin A respectively.
What are the reasons for this poor performance? Jensen et al point the finger at the most likely culprit, the accuracy of the non-polarisable biomolecular force field. Altering parameters such as the interaction strength between permeating ions and the protein has only a very small influence on the calculated current highlighting that simple modifications are unlikely to resolve the discrepancy between simulation and experiment. Deficiencies in the lipid model, such as the overestimation of the membrane dipolar potential, are also discussed; and while these are suggested to be a significant factor in the poor performance of the simulation they do not appear to be the major reason for the underestimation of ion currents. The final suggestion is that polarisable force fields may be required to accurately reproduce permeation rates under experimental conditions. Indeed, in the simple case of gA in which ions permeate one at a time, it would appear plausible that the inclusion of polarisability would improve the results by stabilising ions in the pore and reducing the barriers to permeation. It is not discussed is how much the structure of the proteins change during the simulations, especially under the influence of the electric field. If the structures of the proteins deviate from reality (again due to force field limitations) it is possible that this could also contribute to the poor performance of the simulations, in addition to problems with the ion-protein interactions and lack of polarisability. Given that it has only just become feasible to directly simulate ion currents with non polarisable force fields, it may be some time yet before we know if the use of polarisable ones will make the brute force simulation of physiological processes reliable.
1. M.Ø. Jensen; V. Jogini; M. P. Eastwood and D.E. Shaw. J. Gen. Physiol, 141: 619-632