Biomedical subjects

M S P Sansom

Publications and source records attributed to M S P Sansom.

5 recordsLinked to original sources

PubMed2005

Simulation studies of the interactions between membrane proteins and detergents.

Interactions between membrane proteins and detergents are important in biophysical and structural studies and are also biologically relevant in the context of folding and transport. Despite a paucity of high-resolution data on protein-detergent interactions, novel methods and increased computational power enable simulations to provide a means of understanding such interactions in detail. Simulations have been used to compare the effect of lipid or detergent on the structure and dynamics of membrane proteins. Moreover, some of the longest and most complex simulations to date have been used to observe the spontaneous formation of membrane protein-detergent micelles. Common mechanistic steps in the micelle self-assembly process were identified for both alpha-helical and beta-barrel membrane proteins, and a simple kinetic mechanism was proposed. Recently, simplified (i.e. coarse-grained) models have been utilized to follow long timescale transitions in membrane protein-detergent assemblies.

Bacterial Outer Membrane Proteins↗

PubMed2005

Molecular simulations and lipid-protein interactions: potassium channels and other membrane proteins.

Molecular dynamics simulations may be used to probe the interactions of membrane proteins with lipids and with detergents at atomic resolution. Examples of such simulations for ion channels and for bacterial outer membrane proteins are described. Comparison of simulations of KcsA (an alpha-helical bundle) and OmpA (a beta-barrel) reveals the importance of two classes of side chains in stabilizing interactions with the head groups of lipid molecules: (i) tryptophan and tyrosine; and (ii) arginine and lysine. Arginine residues interacting with lipid phosphate groups play an important role in stabilizing the voltage-sensor domain of the KvAP channel within a bilayer. Simulations of the bacterial potassium channel KcsA reveal specific interactions of phosphatidylglycerol with an acidic lipid-binding site at the interface between adjacent protein monomers. A combination of molecular modelling and simulation reveals a potential phosphatidylinositol 4,5-bisphosphate-binding site on the surface of Kir6.2.

Computer Simulation↗

PubMed2004

Kv channel S6 helix as a molecular switch: simulation studies.

Ion channels form pores of nanoscopic dimensions in biological membranes and play a key role in the physiology of cells. The majority of ion channels are gated, i.e. they contain a molecular switch that allows a transition between a closed (functionally 'off') and open (functionally 'on') state. Comparison of crystal structures of potassium channels suggest that the gating mechanism of voltage-gated potassium (Kv) channels involves a key role for the pore-lining S6 helix. There is a conserved PVP sequence motif in the S6 helix. Molecular dynamics simulations are used here to explore the conformational dynamics of the S6 helix hinge in models of fragments of a Kv channel, namely an S5-P-S6 monomer and an (S5-P-S6)4 tetramer. The latter is a model of the complete pore-forming domain of a Kv channel. All models were simulated embedded in an octane slab (a simple membrane mimetic). The results of these simulations indicate that the PVP motif may form a molecular hinge, even when the S6 helix forms part of a more complex model. The conformational dynamics of S6 are modulated by the remainder of protein, but it remains flexible. These simulation results are compatible with a channel gating model in which S6 bends in the vicinity of the PVP motif in addition to the region around the conserved glycine (G466) that is N-terminal to the PVP motif. This model is supported by comparison of the Kv S6 models with the S6 helix of the bacterial KvAP channel crystal structure. Thus, K channel gating may depend on a complex nanoswitch with three rigid helical sections linked by two molecular hinges.

Journal Article↗

PubMed2003

Pores formed by the nicotinic receptor m2delta Peptide: a molecular dynamics simulation study.

The M2delta peptide self-assembles to form a pentameric bundle of transmembrane alpha-helices that is a model of the pore-lining region of the nicotinic acetylcholine receptor. Long (>15 ns) molecular dynamics simulations of a model of the M2delta(5) bundle in a POPC bilayer have been used to explore the conformational dynamics of the channel assembly. On the timescale of the simulation, the bundle remains relatively stable, with the polar pore-lining side chains remaining exposed to the lumen of the channel. Fluctuations at the helix termini, and in the helix curvature, result in closing/opening transitions at both mouths of the channel, on a timescale of approximately 10 ns. On average, water within the pore lumen diffuses approximately 4x more slowly than water outside the channel. Examination of pore water trajectories reveals both single-file and path-crossing regimes to occur at different times within the simulation.

Amino Acid Sequence↗

PubMed2002

Bundles consisting of extended transmembrane segments of Vpu from HIV-1: computer simulations and conductance measurements.

Part of the genome of the human immunodeficiency virus type 1 (HIV-1) encodes for a short membrane protein Vpu, which has a length of 81 amino acids. It has two functional roles: (i) to downregulate CD4 and (ii) to support particle release. These roles are attributed to two distinct domains of the peptide, the cytoplasmic and transmembrane (TM) domains, respectively. It has been suggested that the enhanced particle release function is linked to the ion channel activity of Vpu, with a slight preference for cations over anions. To allow ion flux across the membrane Vpu would be required to assemble in homooligomers to form functional water-filled pores. In this study molecular dynamics simulations are used to address the role of particular amino acids in 4, 5, and 6 TM helix bundle structures. The helices (Vpu(6-33)) are extended to include hydrophilic residues such as Glu, Tyr, and Arg (EYR motif). Our simulations indicate that this motif destabilizes the bundles at their C-terminal ends. The arginines point into the pore to form a positive charged ring that could act as a putative selectivity filter. The helices of the bundles adopt slightly higher average tilt angles with decreasing number of helices. We also suggest that the helices are kinked. Conductance measurements on a peptide (Vpu(1-32)) reconstituted into lipid membranes show that the peptide forms ion channels with several conductance levels.

Amino Acid Sequence↗