Accurate Evaluation of Ion Conductivity of the Gramicidin A Channel Using a Polarizable Force Field without Any Corrections

Abstract

Classical molecular dynamic (MD) simulation of membrane proteins faces significant challenges in accurately reproducing and predicting experimental observables such as ion conductance and permeability due to its incapability of precisely describing the electronic interactions in heterogeneous systems. In this work, the free energy profiles of K(+) and Na(+) permeating through the gramicidin A channel are characterized by using the AMOEBA polarizable force field with a total sampling time of 1 μs. Our results indicated that by explicitly introducing the multipole terms and polarization into the electrostatic potentials, the permeation free energy barrier of K(+) through the gA channel is considerably reduced compared to the overestimated results obtained from the fixed-charge model. Moreover, the estimated maximum conductance, without any corrections, for both K(+) and Na(+) passing through the gA channel are much closer to the experimental results than any classical MD simulations, demonstrating the power of AMOEBA in investigating the membrane proteins.

Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation

“…; Peng et al . ), demonstrating reduced free energy barriers and thus providing more accurate channel conductance. And, fully polarizable MD simulations were reported recently for other ion channels as well (Dhakshnamoorthy et al .…”

Thermodynamic integration network approach to ion transport through protein channels: Perspectives and limits

“…We note that for the H2H conformation, larger values have also been computed, ranging from 12 kcal mol –1 for K + to 15 kcal mol –1 for Na + transfer . A considerable reduction of the computed barrier by using a polarizable force field (Amoeba vs. Charmm) has been reported by Peng et al Differences in the free energies between ions localized in the protein channel and solvated in bulk water have been addressed by Giorgino and De Fabritiis and De Fabritiis et al by steered MD. The authors arrive at 14 and 19 kcal mol –1 , respectively.…”

Polarizable force field development for lipids and their efficient applications in membrane proteins

“…In an unpublished work of our lab, parameters for POPC were proposed. And we have reported that the free energy profiles of K + and Na + permeating through the gramicidin A channel embedded in DMPC are characterized by using the AMOEBA polarizable force field …”

“…Polarization may contribute 10–20% of the total interaction energy, and if the system is charged, which means polarization and electrostatic are critical, the contribution may increase to 40% . The AMOEBA POPC and DMPC force field have been constructed in 2016, and the PMF results of Na + and K + pass through gA channel show that the parameters of lipid are reliable, and the enhanced sampling algorithms based on AMOEBA has been implemented in the OpenMM . In these cases, the polarizable force fields can further promote the accuracy of the binding free energy of membrane protein with the ligand to achieve near‐quantitative agreement with experimental binding free energy values .…”