Quantum Calculations as a Tool in Structural Biology
EMSL Project ID
34918
Abstract
We are planning to continue work on understanding ion channels by application of quantum calculations to these critically important proteins. Ion channels play a key role in essentially every living cell. Malfunctioning ion channels produce numerous diseases, not limited to diseases of excitable tissue, such as nerve and heart. Second, we will have prepared the tools for a much more accurate calculation of protein structure and function by improving hydrogen bond and salt bridge potentials so that they can be used in simulations, which allow many more atoms to be included in calculations. This applies to both biological problems and surface chemistry science themes. We have already completed enough of these calculations to be confident that the results are significant. Two questions have been raised about whether the results would accord with experiment: i) quantum optimizations give results at 0 K, not room temperature; ii) they require truncation of the system. One aim of the next year's work is to answer these comments. Fortunately, we already have results for enough systems, with comparison to experimental work, to have a high degree of confidence that these objections can be answered successfully; two new collaborative agreements will make possible more directed experiments, and a third will allow incorporation of some of the results into improved simulations. We are already doing frequency calculations that allow us to bring the optimizations to room temperature for thermodynamic quantities. A major part of the next year's work will be devoted to demonstrating the quality of the calculations by further comparison with experimental results. Also, we are developing potentials for hydrogen bonds and salt bridges that include the effects of surroundings, for use in simulations. We expect to add an extremely valuable technique to those available for understanding the functioning not only of ion channels, but of proteins more generally. Standard molecular dynamics (MD) potentials are parameterized for bulk solutions; we have shown that these can be significantly in error in confined spaces. The potentials that we have already found are being prepared for use in Monte Carlo simulations; we expect to complete this in the next year. The necessary neighbor tracking program has been written, and it should be in usable form by the start of the first year of this project. Once this is available, QM/MM methods will also be more accurate; we will adapt those as well to our problem.
We have proposed a mechanism for gating (opening and closing) of ion channels that includes a non-standard characteristic, proton transport as gating current; as evidence grows, our proposal seems more and more viable. Calculations on the voltage sensing domain (VSD) of an ion channel are needed; a very large number of experimental groups have worked on channel gating for several decades, with results that still leave the mechanism ambiguous. More recently, we have worked on the problem of how a channel chooses between K+ and Na+ (selectivity), second of the three fundamental questions in understanding ion channels (the third is conduction). The results so far, on the channel "cavity", point the way to what is needed for understanding selectivity; the "selectivity filter" itself remains to be done.
In the next year, therefore, we will be able to test some of the main ideas on which we have been working. Two additional years may make it possible to completely reap the benefits of the past five years of effort, and the computer time so far invested.
Project Details
Project type
Capability Research
Start Date
2009-10-01
End Date
2012-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Kariev, AM and Green, ME. Poster presentation at the Biophysical Society national meeting 2013:THE IMPORTANCE OF THE PROLINES IN THE PVPV SEQUENCE, AS SHOWN BY COMPUTATIONAL MUTATION, AND THE ROLE OF A HISTIDINE IN GATING: PART 1: THE HISTIDINE SWITCH.
Kariev, AM and Green, ME. Poster presentation at the Biophysical Society national meeting 2013: WATER AT THE POTASSIUM CHANNEL GATE: QUANTUM CALCULATIONS SHOW OSCILLATING WATER STRUCTURE, AND A P407V MUTATION
ALTERS THE WATER STRUCTURE. PART 2: PROLINES AND WATER IN THE GATE
Kariev AM, and ME Green. 2009. "Quantum calculations on water in the KcsA channel cavity with permeant and non-permeant ions." Biochimica et Biophysica Acta--Biomembranes 1788(5):1188-92. doi:10.1016/j.bbamem.2008.12.015
Kariev AM, and ME Green. 2012. "Voltage Gated Ion Channel Function: Gating, Conduction, and the Role of Water and Protons." International Journal of Molecular Sciences 13(2):1680-1709. doi:10.3390/ijms13021680
Liao S, and ME Green. 2011. "Quantum Calculations on Salt Bridges with Water: Potentials, Structure, and Properties." Computational and Theoretical Chemistry 963(1):207-214. doi:10.1016/j.comptc.2010.10.028