Biomedical subjects

George Patargias

Publications and source records attributed to George Patargias.

5 recordsLinked to original sources

PubMed2006

Protein-protein interactions: modeling the hepatitis C virus ion channel p7.

The p7 protein is a small ion-channel-forming membrane polypeptide encoded by the hepatitis C virus which consists of two transmembrane alpha-helices, TM1 and TM2, and can be blocked by long-alkyl-chain iminosugar derivatives. The length of TM1 and TM2 was estimated by employing different secondary structure prediction algorithms and is proposed to span from Ala-10 to Leu-32 for TM1 and from Trp-36 to Pro-58 for TM2. A configurational search protocol based on simulated annealing combined with short restrained molecular dynamics simulations is used in addition to protein-protein docking to investigate the packing of TM1/TM2. Full p7 oligomeric bundles were generated, and in the most plausible models serines and threonines are facing the hydrophilic pore. In these models, His-17 would be a pore-facing residue, suggesting that p7 may be sensitive to pH in respect to its function.

Amantadine↗

PubMed2005

Molecular dynamics simulations of GlpF in a micelle vs in a bilayer: conformational dynamics of a membrane protein as a function of environment.

Octyl glucoside (OG) is a detergent widely employed in structural and functional studies of membrane proteins. To better understand the nature of protein-OG interactions, molecular dynamics simulations (duration 10 ns) have been used to explore an alpha-helical membrane protein, GlpF, in OG micelles and in DMPC bilayers. Greater conformational drift of the extramembraneous protein loops, from the initial X-ray structure, is seen for the GlpF-OG simulations than for the GlpF-DMPC simulation. The mobility of the transmembrane alpha-helices is approximately 1.3x higher in the GlpF-OG than the GlpF-DMPC simulations. The detergent is seen to form an irregular torus around the protein. The presence of the protein leads to a small perturbation in the behavior of the alkyl chains in the OG micelle, namely an approximately 15% increase in the trans-gauche(-)-gauche(+) transition time. Aromatic side chains (Trp, Tyr) and basic side chains (Arg, Lys) play an important role in both protein-detergent (OG) and protein-lipid (DMPC) interactions.

Aquaporins↗

PubMed2005

Membrane protein structure quality in molecular dynamics simulation.

Our goal was to assess the relationship between membrane protein quality, output from protein quality checkers and output from molecular dynamics (MD) simulations. Membrane transport proteins are essential for a wide range of cellular processes. Structural features of integral membrane proteins are still under-explored due to experimental limitations in structure determination. Computational techniques can be used to exploit biochemical and medium resolution structural data, as well as sequence homology to known structures, and enable us to explore the structure-function relationships in several transmembrane proteins. The quality of the models produced is vitally important to obtain reliable predictions. An examination of the relationship between model stability in molecular dynamics (MD) simulations derived from RMSD (root mean squared deviation) and structure quality assessment from various protein quality checkers was undertaken. The results were compared to membrane protein structures, solved at various resolution, by either X-ray or electron diffraction techniques. The checking programs could predict the potential success of MD in making functional conclusions. MD stability was shown to be a good indicator for the quality of structures. The quality was also shown to be dependent on the resolution at which the structures were determined.

Computer Simulation↗

PubMed2004

Conformational sampling and dynamics of membrane proteins from 10-nanosecond computer simulations.

In the current report, we provide a quantitative analysis of the convergence of the sampling of conformational space accomplished in molecular dynamics simulations of membrane proteins of duration in the order of 10 nanoseconds. A set of proteins of diverse size and topology is considered, ranging from helical pores such as gramicidin and small beta-barrels such as OmpT, to larger and more complex structures such as rhodopsin and FepA. Principal component analysis of the C(alpha)-atom trajectories was employed to assess the convergence of the conformational sampling in both the transmembrane domains and the whole proteins, while the time-dependence of the average structure was analyzed to obtain single-domain information. The membrane-embedded regions, particularly those of small or structurally simple proteins, were found to achieve reasonable convergence. By contrast, extra-membranous domains lacking secondary structure are often markedly under-sampled, exhibiting a continuous structural drift. This drift results in a significant imprecision in the calculated B-factors, which detracts from any quantitative comparison to experimental data. In view of such limitations, we suggest that similar analyses may be valuable in simulation studies of membrane protein dynamics, in order to attach a level of confidence to any biologically relevant observations.

Computer Simulation↗

PubMed2002

Water in ion channels and pores--simulation studies.

The microscopic properties of water in narrow pores are relevant to the function of ion channels and related membrane transport proteins. The emergence of several high-resolution structures allows one to perform molecular dynamics simulation studies of water in such pores. Simulations of bundles of parallel alpha-helical peptides (e.g. alamethicin) have enabled development of methodologies and concepts appropriate to such investigations. In the narrow channels formed by such bundles, water molecules exhibit reduced rotational and translation motion. This reduction in water mobility may be a general property of narrow pores. We have used simplified channel models to explore the role of hydrophobicity/hydrophilicity in the entry of water into pores. Narrow pores with a hydrophobic lining, although physically open, may not admit water molecules, acting as a 'hydrophobic gate' that prevents water and ion permeation. Such a gate can be opened either by widening the pore or making its lining more polar. Simulations have been used to explore the behaviour of water in GlpF, a member of the aquaporin family of water pores, and OmpA, a bacterial outer membrane protein. Preliminary results suggest that a continuous water wire is not formed within the amphipathic GlpF pore. Simulations of OmpA, in which polar residues line the channel, indicate that a small conformational change in one of the channel lining side chains may open the channel. In summary, comparison of the behaviour of water in different narrow transmembrane pores suggests that an amphipathic pore is ideal for water permeation, and that either a highly hydrophobic pore lining or a charged pore-lining region can act as a gate.

Computer Simulation↗