Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel

Pär Bjelkmar, Perttu S Niemelä, Ilpo Vattulainen, Erik Lindahl

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.
Original languageEnglish
JournalPloS Computational Biology
Volume5
Issue number2
Pages (from-to)1-14
ISSN1553-734X
DOIs
Publication statusPublished - 1. Feb 2009

Fingerprint

Kv1.2 Potassium Channel
Membrane Proteins
Lipids
Molecular Dynamics Simulation
Hydrogen Bonding
Hydrogen
Membranes
Research

Keywords

  • Amino Acid Motifs
  • Computer Simulation
  • Energy Transfer
  • Hydrogen Bonding
  • Ion Channel Gating
  • Kv1.2 Potassium Channel
  • Membrane Lipids
  • Membrane Potentials
  • Models, Molecular
  • Static Electricity
  • Structure-Activity Relationship
  • Thermodynamics

Cite this

Bjelkmar, Pär ; Niemelä, Perttu S ; Vattulainen, Ilpo ; Lindahl, Erik. / Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel. In: PloS Computational Biology. 2009 ; Vol. 5, No. 2. pp. 1-14.
@article{ee343a7014c411dfb94c000ea68e967b,
title = "Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel",
abstract = "Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.",
keywords = "Amino Acid Motifs, Computer Simulation, Energy Transfer, Hydrogen Bonding, Ion Channel Gating, Kv1.2 Potassium Channel, Membrane Lipids, Membrane Potentials, Models, Molecular, Static Electricity, Structure-Activity Relationship, Thermodynamics",
author = "P{\"a}r Bjelkmar and Niemel{\"a}, {Perttu S} and Ilpo Vattulainen and Erik Lindahl",
year = "2009",
month = "2",
day = "1",
doi = "10.1371/journal.pcbi.1000289",
language = "English",
volume = "5",
pages = "1--14",
journal = "PLoS Computational Biology",
issn = "1553-734X",
publisher = "Public Library of Science",
number = "2",

}

Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel. / Bjelkmar, Pär; Niemelä, Perttu S; Vattulainen, Ilpo; Lindahl, Erik.

In: PloS Computational Biology, Vol. 5, No. 2, 01.02.2009, p. 1-14.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Conformational changes and slow dynamics through microsecond polarized atomistic molecular simulation of an integral Kv1.2 ion channel

AU - Bjelkmar, Pär

AU - Niemelä, Perttu S

AU - Vattulainen, Ilpo

AU - Lindahl, Erik

PY - 2009/2/1

Y1 - 2009/2/1

N2 - Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

AB - Structure and dynamics of voltage-gated ion channels, in particular the motion of the S4 helix, is a highly interesting and hotly debated topic in current membrane protein research. It has critical implications for insertion and stabilization of membrane proteins as well as for finding how transitions occur in membrane proteins-not to mention numerous applications in drug design. Here, we present a full 1 micros atomic-detail molecular dynamics simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements, including up to 120 degrees rotation of the S4 segment, changes in hydrogen-bonding patterns, but only low amounts of translation. A smaller rotation ( approximately 35 degrees ) of the extracellular end of all S4 segments is present also in a reference 0.5 micros simulation without applied field, which indicates that the crystal structure might be slightly different from the natural state of the voltage sensor. The conformation change upon hyperpolarization is closely coupled to an increase in 3(10) helix contents in S4, starting from the intracellular side. This could support a model for transition from the crystal structure where the hyperpolarization destabilizes S4-lipid hydrogen bonds, which leads to the helix rotating to keep the arginine side chains away from the hydrophobic phase, and the driving force for final relaxation by downward translation is partly entropic, which would explain the slow process. The coordinates of the transmembrane part of the simulated channel actually stay closer to the recently determined higher-resolution Kv1.2 chimera channel than the starting structure for the entire second half of the simulation (0.5-1 micros). Together with lipids binding in matching positions and significant thinning of the membrane also observed in experiments, this provides additional support for the predictive power of microsecond-scale membrane protein simulations.

KW - Amino Acid Motifs

KW - Computer Simulation

KW - Energy Transfer

KW - Hydrogen Bonding

KW - Ion Channel Gating

KW - Kv1.2 Potassium Channel

KW - Membrane Lipids

KW - Membrane Potentials

KW - Models, Molecular

KW - Static Electricity

KW - Structure-Activity Relationship

KW - Thermodynamics

U2 - 10.1371/journal.pcbi.1000289

DO - 10.1371/journal.pcbi.1000289

M3 - Journal article

VL - 5

SP - 1

EP - 14

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 2

ER -