Recovery from slow inactivation in K+ channels is controlled by water molecules

Ostmeyer, Jared; Chakrapani, Sudha; Pan, Albert C.; Perozo, Eduardo; Roux, Benoît

doi:10.1038/nature12395

Recovery from slow inactivation in K⁺ channels is controlled by water molecules

Journal Article · Sun Jul 28 00:00:00 EDT 2013 · Nature (London)

DOI:https://doi.org/10.1038/nature12395· OSTI ID:1564993

Ostmeyer, Jared ^[1]; Chakrapani, Sudha ^[2]; Pan, Albert C. ^[3]; Perozo, Eduardo ^[1]; Roux, Benoît ^[1]

Univ. of Chicago, Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology
Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine, Dept. of Physiology and Biophysics
D.E. Shaw Research, New York, NY (United States)

Application of a specific stimulus opens the intracellular gate of a K⁺ channel (activation), yielding a transient period of ion conduction until the selectivity filter spontaneously undergoes a conformational change towards a non-conductive state (inactivation). Removal of the stimulus closes the gate and allows the selectivity filter to interconvert back to its conductive conformation (recovery). Given that the structural differences between the conductive and inactivated filter are very small, it is unclear why the recovery process can take up to several seconds. The bacterial K⁺ channel KcsA from Streptomyces lividans can be used to help elucidate questions about channel inactivation and recovery at the atomic level. Although KcsA contains only a pore domain, without voltage-sensing machinery, it has the structural elements necessary for ion conduction, activation and inactivation. In this paper we reveal, by means of a series of long molecular dynamics simulations, how the selectivity filter is sterically locked in the inactive conformation by buried water molecules bound behind the selectivity filter. Potential of mean force calculations show how the recovery process is affected by the buried water molecules and the rebinding of an external K⁺ ion. A kinetic model deduced from the simulations shows how releasing the buried water molecules can stretch the timescale of recovery to seconds. This leads to the prediction that reducing the occupancy of the buried water molecules by imposing a high osmotic stress should accelerate the rate of recovery, which was verified experimentally by measuring the recovery rate in the presence of a 2-molar sucrose concentration.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1564993

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7465 Vol. 501; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

References (30)

Scalable molecular dynamics with NAMD Phillips, James C.; Braun, Rosemary; Wang, Wei Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802 https://doi.org/10.1002/jcc.20289	journal	January 2005
A Multipoint Hydrogen-Bond Network Underlying KcsA C-Type Inactivation Cordero-Morales, Julio F.; Jogini, Vishwanath; Chakrapani, Sudha Biophysical Journal, Vol. 100, Issue 10 https://doi.org/10.1016/j.bpj.2011.01.073	journal	May 2011
Dynamics, Energetics, and Selectivity of the Low-K+ KcsA Channel Structure Domene, Carmen; Furini, Simone Journal of Molecular Biology, Vol. 389, Issue 3 https://doi.org/10.1016/j.jmb.2009.04.038	journal	June 2009
Conformational Dynamics in the Selectivity Filter of KcsA in Response to Potassium Ion Concentration Bhate, Manasi P.; Wylie, Benjamin J.; Tian, Lin Journal of Molecular Biology, Vol. 401, Issue 2 https://doi.org/10.1016/j.jmb.2010.06.031	journal	August 2010
Absence of Ion-Binding Affinity in the Putatively Inactivated Low-[K+] Structure of the KcsA Potassium Channel Boiteux, Céline; Bernèche, Simon Structure, Vol. 19, Issue 1 https://doi.org/10.1016/j.str.2010.10.008	journal	January 2011
Modified reconstitution method used in patch-clamp studies of Escherichia coli ion channels Delcour, A. H.; Martinac, B.; Adler, J. Biophysical Journal, Vol. 56, Issue 3 https://doi.org/10.1016/s0006-3495(89)82710-9	journal	September 1989
Recovery from C-type inactivation is modulated by extracellular potassium Levy, D. I.; Deutsch, C. Biophysical Journal, Vol. 70, Issue 2 https://doi.org/10.1016/s0006-3495(96)79619-4	journal	February 1996
Structural mechanism of C-type inactivation in K+ channels Cuello, Luis G.; Jogini, Vishwanath; Cortes, D. Marien Nature, Vol. 466, Issue 7303 https://doi.org/10.1038/nature09153	journal	July 2010
Potassium channel gating: Not an open and shut case Norton, Raymond S.; Gulbis, Jacqueline M. Proceedings of the National Academy of Sciences, Vol. 107, Issue 17 https://doi.org/10.1073/pnas.1002114107	journal	April 2010
A Quantitative Description of KcsA Gating I: Macroscopic Currents Chakrapani, Sudha; Cordero-Morales, Julio F.; Perozo, Eduardo The Journal of General Physiology, Vol. 130, Issue 5 https://doi.org/10.1085/jgp.200709843	journal	October 2007
Exploring atomic resolution physiology on a femtosecond to millisecond timescale using molecular dynamics simulations Dror, Ron O.; Jensen, Morten Ø.; Borhani, David W. The Journal of General Physiology, Vol. 135, Issue 6 https://doi.org/10.1085/jgp.200910373	journal	May 2010
THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal Journal of Computational Chemistry, Vol. 13, Issue 8 https://doi.org/10.1002/jcc.540130812	journal	October 1992
Temperature and pressure dependence of Shaker K + channel N- and C-type inactivation Meyer, Roman; Heinemann, S. H. European Biophysics Journal, Vol. 26, Issue 6 https://doi.org/10.1007/s002490050098	journal	November 1997
The calculation of the potential of mean force using computer simulations Roux, Benoît Computer Physics Communications, Vol. 91, Issue 1-3 https://doi.org/10.1016/0010-4655(95)00053-I	journal	September 1995
Modified reconstitution method used in patch-clamp studies of Escherichia coli ion channels Delcour, A. H.; Martinac, B.; Adler, J. Biophysical Journal, Vol. 56, Issue 3 https://doi.org/10.1016/S0006-3495(89)82710-9	journal	September 1989
Recovery from C-type inactivation is modulated by extracellular potassium Levy, D. I.; Deutsch, C. Biophysical Journal, Vol. 70, Issue 2 https://doi.org/10.1016/S0006-3495(96)79619-4	journal	February 1996
Calculation of Free Energy Landscape in Multi-Dimensions with Hamiltonian-Exchange Umbrella Sampling on Petascale Supercomputer Jiang, Wei; Luo, Yun; Maragliano, Luca Journal of Chemical Theory and Computation, Vol. 8, Issue 11 https://doi.org/10.1021/ct300468g	journal	October 2012
Ion transport in a gramicidin-like channel: dynamics and mobility Roux, Benoit; Karplus, Martin The Journal of Physical Chemistry, Vol. 95, Issue 12 https://doi.org/10.1021/j100165a049	journal	June 1991
Effects of Solvent Viscosity on Protein Dynamics: Infrared Vibrational Echo Experiments and Theory Rector, K. D.; Jiang, Jianwen; Berg, Mark A. The Journal of Physical Chemistry B, Vol. 105, Issue 5 https://doi.org/10.1021/jp0023563	journal	February 2001
All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins ^† MacKerell, A. D.; Bashford, D.; Bellott, M. The Journal of Physical Chemistry B, Vol. 102, Issue 18 https://doi.org/10.1021/jp973084f	journal	April 1998
Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution Zhou, Yufeng; Morais-Cabral, João H.; Kaufman, Amelia Nature, Vol. 414, Issue 6859 https://doi.org/10.1038/35102009	journal	November 2001
Structural basis for the coupling between activation and inactivation gates in K+ channels Cuello, Luis G.; Jogini, Vishwanath; Cortes, D. Marien Nature, Vol. 466, Issue 7303 https://doi.org/10.1038/nature09136	journal	July 2010
On the structural basis of modal gating behavior in K+ channels Chakrapani, Sudha; Cordero-Morales, Julio F.; Jogini, Vishwanath Nature Structural & Molecular Biology, Vol. 18, Issue 1 https://doi.org/10.1038/nsmb.1968	journal	December 2010
Molecular determinants of gating at the potassium-channel selectivity filter Cordero-Morales, Julio F.; Cuello, Luis G.; Zhao, Yanxiang Nature Structural & Molecular Biology, Vol. 13, Issue 4 https://doi.org/10.1038/nsmb1069	journal	March 2006
Molecular driving forces determining potassium channel slow inactivation Cordero-Morales, Julio F.; Jogini, Vishwanath; Lewis, Anthony Nature Structural & Molecular Biology, Vol. 14, Issue 11 https://doi.org/10.1038/nsmb1309	journal	October 2007
Structural basis underlying the dual gate properties of KcsA Imai, S.; Osawa, M.; Takeuchi, K. Proceedings of the National Academy of Sciences, Vol. 107, Issue 14 https://doi.org/10.1073/pnas.0911270107	journal	March 2010
Molecular Architecture of Full-Length KcsA : Role of Cytoplasmic Domains in Ion Permeation and Activation Gating Cortes, D. Marien; Cuello, Luis G.; Perozo, Eduardo The Journal of General Physiology, Vol. 117, Issue 2 https://doi.org/10.1085/jgp.117.2.165	journal	January 2001
A Quantitative Description of KcsA Gating II: Single-Channel Currents Chakrapani, Sudha; Cordero-Morales, Julio F.; Perozo, Eduardo The Journal of General Physiology, Vol. 130, Issue 5 https://doi.org/10.1085/jgp.200709844	journal	October 2007
Thermodynamic coupling between activation and inactivation gating in potassium channels revealed by free energy molecular dynamics simulations Pan, Albert C.; Cuello, Luis G.; Perozo, Eduardo The Journal of General Physiology, Vol. 138, Issue 6 https://doi.org/10.1085/jgp.201110670	journal	November 2011
Millisecond-scale molecular dynamics simulations on Anton Shaw, David E.; Bowers, Kevin J.; Chow, Edmond Proceedings of the Conference on High Performance Computing Networking, Storage and Analysis - SC '09 https://doi.org/10.1145/1654059.1654126	conference	January 2009

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