Effect of Intercalated Water on Potassium Ion Transport through Kv1.2 Channels Studied via On-the-Fly Free-Energy Parametrization

J Chem Theory Comput. 2018 May 8;14(5):2743-2750. doi: 10.1021/acs.jctc.8b00024. Epub 2018 Apr 3.


We introduce a two-dimensional version of the method called on-the-fly free energy parametrization (OTFP) to reconstruct free-energy surfaces using Molecular Dynamics simulations, which we name OTFP-2D. We first test the new method by reconstructing the well-known dihedral angles free energy surface of solvated alanine dipeptide. Then, we use it to investigate the process of K+ ions translocation inside the Kv1.2 channel. By comparing a series of two-dimensional free energy surfaces for ion movement calculated with different conditions on the intercalated water molecules, we first recapitulate the widely accepted knock-on mechanism for ion translocation and then confirm that permeation occurs with water molecules alternated among the ions, in accordance with the latest experimental findings. From a methodological standpoint, our new OTFP-2D algorithm demonstrates the excellent sampling acceleration of temperature-accelerated molecular dynamics and the ability to efficiently compute 2D free-energy surfaces. It will therefore be useful in large variety complex biomacromolecular simulations.

Publication types

  • Validation Study

MeSH terms

  • Alanine / chemistry
  • Dipeptides / chemistry
  • Ion Transport
  • Kv1.2 Potassium Channel / chemistry*
  • Molecular Dynamics Simulation
  • Potassium / chemistry*
  • Water / chemistry*


  • Dipeptides
  • Kv1.2 Potassium Channel
  • Water
  • Alanine
  • Potassium