Biomedical subjects

Indira H Shrivastava

Publications and source records attributed to Indira H Shrivastava.

5 recordsLinked to original sources

PubMed2002

Potassium channels: structures, models, simulations.

Potassium channels have been studied intensively in terms of the relationship between molecular structure and physiological function. They provide an opportunity to integrate structural and computational studies in order to arrive at an atomic resolution description of mechanism. We review recent progress in K channel structural studies, focussing on the bacterial channel KcsA. Structural studies can be extended via use of computational (i.e. molecular simulation) approaches in order to provide a perspective on aspects of channel function such as permeation, selectivity, block and gating. Results from molecular dynamics simulations are shown to be in good agreement with recent structural studies of KcsA in terms of the interactions of K(+) ions with binding sites within the selectivity filter of the channel, and in revealing the importance of filter flexibility in channel function. We discuss how the KcsA structure may be used as a template for developing structural models of other families of K channels. Progress in this area is explored via two examples: inward rectifier (Kir) and voltage-gated (Kv) potassium channels. A brief account of structural studies of ancillary domains and subunits of K channels is provided.

Amino Acid Sequence↗

PubMed2002

Molecular dynamics simulations and KcsA channel gating.

The gating mechanism of a bacterial potassium channel, KcsA, has been investigated via multi-nanosecond molecular dynamic simulations of the channel molecules embedded in a fully solvated palmitoyloleoylphosphatidylcholine bilayer. Four events are seen in which a cation (K(+) or, in one case, Na(+)) initially present in the central cavity exits through the intracellular mouth (the presumed gate) of the channel. Whilst in the cavity a cation interacts with the sidechain T107 O gamma atom of one of the subunits prior to its exit from the channel. Secondary structure analysis as a function of time reveals a break in the helicity of one of the M2 helices. This break is expected to lend flexibility to the helices, enabling them to "open" (minimum pore radius >0.13 nm) and "close" (minimum pore radius <0.13 nm) the channel. Fluctuations in the pore radius at the intracellular gate region are of the order of 0.05 nm, with an average radius in the region of the gate of ca. 0.1 nm. However, around the time of exit of a cation, the pore widens to about 0.15 nm. The distances between the C alpha atoms of the inner helices M2 reveal a coupled increase and decrease between the opposite pair of helices at about the time of exit of the ion. This suggests a breathing motion of the M2 helices that may form the basis for a gating mechanism.

Bacterial Proteins↗

PubMed2002

Ion channels: frozen motion.

Our understanding of ion permeation through K(+) channels, and by extension through other channels, is advancing rapidly. New structural studies, together with computer simulations, have provided profound insights into ion conduction mechanisms.

Crystallography, X-Ray↗

PubMed2002

Conformational dynamics of helix S6 from Shaker potassium channel: simulation studies.

Prolines in transmembrane (TM) alpha-helices are believed to play an important structural and/or functional role in membrane proteins. At a structural level a proline residue distorts alpha-helical structure due to the loss of at least one stabilizing backbone hydrogen bond, and introduces flexibility in the helix that may result in substantial kink and swivel motions about the effective "hinge." At a functional level, for example in Kv channels, it is believed that proline-induced molecular hinges may have a direct role in gating, i.e., the conformational change linked to opening/closing the channel to movement of ions. In this article we study the conformational dynamics of the S6 TM helix from of the Kv channel Shaker, which possesses the motif PVP--a motif that is conserved in Kv channels. We perform multiple molecular dynamics simulations of single S6 helices in a membrane-mimetic environment in order to effectively map the kink-swivel conformational space of the protein, exploiting the ability of multiple simulations to achieve greater sampling. We show that the presence of proline locally perturbs the helix, disrupting local dihedral angles and producing local twist and unwinding in the region of the hinge--an effect that is relaxed with distance from the PVP motif. We furthermore show that motions about the hinge are highly anisotropic, reflecting a preferred region of kink-swivel conformation space that may have implications for the gating process.

Models, Molecular↗

PubMed2002

K(+) versus Na(+) ions in a K channel selectivity filter: a simulation study.

Molecular dynamics simulations of a bacterial potassium channel (KcsA) embedded in a phospholipid bilayer reveal significant differences in interactions of the selectivity filter with K(+) compared with Na(+) ions. K(+) ions and water molecules within the filter undergo concerted single-file motion in which they translocate between adjacent sites within the filter on a nanosecond timescale. In contrast, Na(+) ions remain bound to sites within the filter and do not exhibit translocation on a nanosecond timescale. Furthermore, entry of a K(+) ion into the filter from the extracellular mouth is observed, whereas this does not occur for a Na(+) ion. Whereas K(+) ions prefer to sit within a cage of eight oxygen atoms of the filter, Na(+) ions prefer to interact with a ring of four oxygen atoms plus two water molecules. These differences in interactions in the selectivity filter may contribute to the selectivity of KcsA for K(+) ions (in addition to the differences in dehydration energy between K(+) and Na(+)) and the block of KcsA by internal Na(+) ions. In our simulations the selectivity filter exhibits significant flexibility in response to changes in ion/protein interactions, with a somewhat greater distortion induced by Na(+) than by K(+) ions.

Biophysical Phenomena↗