Simulations of Ion Permeation Through a Potassium Channel: Molecular Dynamics of KcsA in a Phospholipid Bilayer

Abstract

Potassium channels enable K(+) ions to move passively across biological membranes. Multiple nanosecond-duration molecular dynamics simulations (total simulation time 5 ns) of a bacterial potassium channel (KcsA) embedded in a phospholipid bilayer reveal motions of ions, water, and protein. Comparison of simulations with and without K(+) ions indicate that the absence of ions destabilizes the structure of the selectivity filter. Within the selectivity filter, K(+) ions interact with the backbone (carbonyl) oxygens, and with the side-chain oxygen of T75. Concerted single-file motions of water molecules and K(+) ions within the selectivity filter of the channel occur on a 100-ps time scale. In a simulation with three K(+) ions (initially two in the filter and one in the cavity), the ion within the central cavity leaves the channel via its intracellular mouth after approximately 900 ps; within the cavity this ion interacts with the Ogamma atoms of two T107 side chains, revealing a favorable site within the otherwise hydrophobically lined cavity. Exit of this ion from the channel is enabled by a transient increase in the diameter of the intracellular mouth. Such "breathing" motions may form the molecular basis of channel gating.

Cooperative transport in a potassium ion channel

“…Similar coupled translocation has been observed in other simulations. 39,40 C. Coupling of carbonyl groups with water and K + Previous MD simulations studies 39,40 have shown that during the motions of the ions subtle changes in the backbone conformation of the selectivity filter can appear, which indicates towards a coupling between ion permeation and positional changes of the carbonyl groups. Similar findings can be reported from our simulations.…”

A microscopic view of ion conduction through the K+ channel

“…The availability of high-resolution crystallographic structures (2)(3)(4), together with the development of sophisticated computer models (5)(6)(7)(8)(9)(10), is providing us with a unique opportunity to refine our understanding of these systems at an unprecedented level. Although the complexity of these channels does present a formidable challenge to biomolecular modeling, it is particularly encouraging to note that many of the recent results from molecular dynamics (MD) simulations based on realistic all-atom models have been consistent with the information emerging from higher-resolution structural data (for a recent review, see ref.…”

“…At the present time, this cannot be done by using simple ''brute-force'' MD simulations (11). According to single-channel measurements, the ionic flux across the KcsA under a transmembrane potential of 100 mV corresponds to the net translocation of approximately one ion in 10-20 ns (14), which is on the order of a typical MD trajectory (6)(7)(8)(9)(10). Despite the steady increase in computer power, the direct simulation of ionic fluxes across a selective biological channel with all-atom MD remains computationally prohibitive.…”

A gating mechanism proposed from a simulation of a human α7 nicotinic acetylcholine receptor

“…Transport processes for membrane proteins are somewhat accessible within the time-scale limitations of all-atom simulations, and MD has had much success in analyzing these, for example, in K channels (27,28) and aquaporins (29)(30)(31), where the mechanism was first shown in a homology model (30). Previous studies of the LBD in MD have yielded valuable information about its function (32,33).…”