Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels

J Chem Inf Model. 2015 Apr 27;55(4):814-22. doi: 10.1021/acs.jcim.5b00010. Epub 2015 Apr 3.

Abstract

Prokaryotic inwardly rectifying (KirBac) potassium channels are homologous to mammalian Kir channels. Their activity is controlled by dynamical conformational changes that regulate ion flow through a central pore. Understanding the dynamical rearrangements of Kir channels during gating requires high-resolution structure information from channels crystallized in different conformations and insight into the transition steps, which are difficult to access experimentally. In this study, we use MD simulations on wild type KirBac1.1 and an activatory mutant to investigate activation gating of KirBac channels. Full atomistic MD simulations revealed that introducing glutamate in position 143 causes significant widening at the helix bundle crossing gate, enabling water flux into the cavity. Further, global rearrangements including a twisting motion as well as local rearrangements at the subunit interface in the cytoplasmic domain were observed. These structural rearrangements are similar to recently reported KirBac3.1 crystal structures in closed and open conformation, suggesting that our simulations capture major conformational changes during KirBac1.1 opening. In addition, an important role of protein-lipid interactions during gating was observed. Slide-helix and C-linker interactions with lipids were strengthened during activation gating.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • Hydrogen Bonding
  • Ion Channel Gating*
  • Lipid Metabolism
  • Molecular Dynamics Simulation*
  • Mutant Proteins / chemistry*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation*
  • Potassium Channels, Inwardly Rectifying / chemistry*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Rotation
  • Thermodynamics

Substances

  • Mutant Proteins
  • Potassium Channels, Inwardly Rectifying