Hello, A change in allocation has been requested: Requester: roux (Benoit Roux) Project: kcsa Title: Computational study of ion selectivity in the KcsA channel Description: Understanding quantitatively the microscopic factors controlling ion selectivity remains a great challenge. In simple terms, the concept of selectivity means that the "correct" ion, is able to binding more favorably than an "incorrect" ion. At a physical level, it is to be anticipated that energetics and solvation play a key role in this process, although different aspects of energetics may be highlighted by the various experimental methods used to probe the system. Barium (Ba2+) is a divalent ion that is known to block the normal conduction of K+ ion. Altering the concentration of K+ on one side of the channel release the block by pushing the Ba2+ to the other side. Pushing the Ba2+ can also be done by Na+, but it is more difficult because the channel prefer (is selective) to K+. This technique has been used experimentally to probe the selectivity of the channel for K+ over Na+. But this process is not fully understood at the microscopic level, which undermines a robust interpretation of the experimental results. Our goal is to compute the mechanism of barium blockade in the KcsA channel. The most informative strategy to address issues of ion selectivity is to compute the multi-ion PMF corresponding to the microscopic process in question (Berneche and Roux, Nature 2001). We carry those type of calculations using umbrella sampling MD simulations. Recently, we have been able to do this with the extremely scalable strategy based on hamiltonian replica-exchange MD using CHARMM/REPD. Tasks to do: We will compute the multi-ion PM for a channel blocked by one Ba2+ in the presence of K+. We will also compute the multi-ion PM for a channel blocked by one Ba2+ in the presence of Na+. The comparison between the two PMFs will reveal the microscopic basis for the unblocking effect of the added ion (K+ or Na+). A 2-ion potential of mean force with one Ba2+ and one K+ going through the channel: 350 windows/replica One replica use one node (8 cores). Sampling of 1 ns takes 50 hours. Total needed: 50*350*8 = 140,000 core-hours A 2-ion potential of mean force with one Ba2+ and one Na+ going through the channel: 350 windows/replica One replica use one node (8 cores). Sampling of 1 ns takes 50 hours. Total needed: 50*350*8 = 140,000 core-hours Total needed for this project 280,000 core-hours This project is ready to go, so we could use the resource immediately, starting with the first quarter. Software requirements CHARMM/REPD Expected number of project members: Benoit Roux, and Chris Rowley REFERENCES Noskov, SY; Berneche, S; Roux, B Control of ion selectivity in potassium channels by electrostatic and dynamic properties of carbonyl ligands. NATURE Volume: 431 Issue: 7010 Pages: 830-834 Published: OCT 14 2004 Egwolf, B; Roux, B Ion Selectivity of the KcsA Channel: A Perspective from Multi-Ion Free Energy Landscapes. JOURNAL OF MOLECULAR BIOLOGY Volume: 401 Issue: 5 Pages: 831-842 Published: 2010 Current: undetermined amount Justification: Requested: 100000 A specific reason has been given: The majority of this project is carried out elsewhere, but there are a few things that benefit from a LCRC allocation to maintain continuity. This needs to be approved and the final allocation amount decided upon. Thank You, The LCRC Accounts System