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.

Disposition kinetics and urinary excretion of pefloxacin after intravenous injection in crossbred calves.

The disposition kinetics and urinary excretion of pefloxacin after a single intravenous administration of 5 mg/kg were investigated in crossbred calves and an appropriate dosage regimen was calculated. At 1 min after injection, the concentration of pefloxacin in the plasma was 18.95 +/- 0.892 microg/ml, which declined to 0.13 +/- 0.02 microg/ml at 10 h. The pefloxacin was rapidly distributed from the blood to the tissue compartment as shown by the high values for the initial distribution coefficient, alpha (12.1 +/- 1.21 h-1) and the constant for the rate of transfer of drug from the central to the peripheral compartment, K12 (8.49 +/- 0.99 h ). The elimination half-life and volume of distribution were 2.21+/- 0.111 h and 1.44 +/- 0.084 L/kg, respectively. The total body clearance (ClB) and the ratio of the drug present in the peripheral to that in the central compartment (P/C ratio) were 0.454 +/- 0.026 L/kg h) and 5.52 +/- 0.519, respectively. On the basis of the pharmacokinetic parameters obtained in the present study, an appropriate intravenous dosage regimen for pefloxacin in cattle for most of the bacteria sensitive to it would be 6.4 mg/kg repeated at 12 h intervals.