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Victor B Luzhkov

Publications and source records attributed to Victor B Luzhkov.

6 recordsLinked to original sources
PubMed2006

Computational study of the binding affinity and selectivity of the bacterial ammonium transporter AmtB.

We report results from microscopic molecular dynamics and free energy perturbation simulations of substrate binding and selectivity for the Escherichia coli high-affinity ammonium transporter AmtB. The simulation system consists of the protein embedded in a model membrane/water surrounding. The calculated absolute binding free energies for the external NH(4)(+) ions are between -5.8 and -7.3 kcal/mol and are in close agreement with experimental data. The apparent pK(a) of the bound NH(4)(+) increases by more than 4 units, indicating a preference for binding ammonium ion and not neutral ammonia. The external binding site is also selective for NH(4)(+) toward monovalent metal cations by 2.4-4.4 kcal/mol. The externally bound NH(4)(+) shows strong electrostatic interactions with the proximal buried Asp160, stabilized in the anionic form, whereas the interactions with the aromatic rings of Phe107 and Trp148, lining the binding cavity, are less pronounced. Simulated mutation of the highly conserved Asp160 to Asn reduces the pK(a) of the bound ammonium ion by approximately 7 units and causes loss of its binding. The calculations further predict that the substrate affinity of E. coli AmtB depends on the ionization state of external histidines. The computed free energies of hypothetical intermediate states related to transfer of NH(3), NH(4)(+), or H(2)O from the external binding site to the first position inside the internal channel pore favor permeation of the neutral species through the channel interior. However, the predicted change in the apparent pK(a) of NH(4)(+) upon translocation from the external site, Am1, to the first internal site, Am2, indicates that ammonium ion becomes deprotonated only when it enters the channel interior.

Binding Sites↗
PubMed2003

Structure-activity relationship for extracellular block of K+ channels by tetraalkylammonium ions.

External tetraalkylammonium ion binding to potassium channels is studied using microscopic molecular modelling methods and the experimental structure of the KcsA channel. Relative binding free energies of the KcsA complexes with Me4N+, Et4N+, and n-Pr4N+ are calculated with the molecular dynamics free energy perturbation approach together with automated ligand docking. The four-fold symmetry of the entrance cavity formed by the Tyr82 residues is found to provide stronger binding for the D2d than for the S4 conformation of the ligands. In agreement with experiment the Et4N+ blocker shows several kcal/mol better binding than the other tetraalkylammonium ions.

Bacterial Proteins↗
PubMed2003

Computational modelling of the open-state Kv 1.5 ion channel block by bupivacaine.

Binding of R(+)-bupivacaine to open-state homology models of the mammalian K(v)1.5 membrane ion channel is studied using automated docking and molecular dynamics (MD) methods. Homology models of K(v)1.5 are built using the 3D structures of the KcsA and MthK channels as a template. The packing of transmembrane (TM) alpha-helices in the KcsA structure corresponds to a closed channel state. Opening of the channel may be reached by a conformational transition yielding a bent structure of the internal S6 helices. Our first model of the K(v) open state involves a PVP-type of bending hinge in the internal helices, while the second model corresponds to a Gly-type of bending hinge as found in the MthK channel. Ligand binding to these models is probed using the common local anaesthetic bupivacaine, where blocker binding from the intracellular side of the channel is considered. Conformational properties and partial atomic charges of bupivacaine are determined from quantum mechanical HF/6-31G* calculations with inclusion of solvent effects. The automated docking and MD calculations for the PVP-bend model predict that bupivacaine could bind either in the central cavity or in the PVP region of the channel pore. Linear interaction energy (LIE) estimates of the binding free energies for bupivacaine predict strongest binding to the PVP region. Surprisingly, no binding is predicted for the Gly-bend model. These results are discussed in light of electrophysiological data which show that the K(v)1.5 channel is unable to close when bupivacaine is bound.

Amino Acid Sequence↗
PubMed2002

Computational study of the influence of solvent on (16)O/(18)O equilibrium isotope effects in phosphate deprotonation reactions.

Results from theoretical calculations of (16)O/(18)O equilibrium isotope effects (EIEs) on deprotonation of phosphate and methyl phosphate monoanions as well as their deuterated counterparts are reported. The EIEs are calculated from the Bigeleisen equation using harmonic vibrational frequencies from several quantum mechanical methods (HF, DFT, MP2, and AM1). All methods correctly predict the qualitative trends in the EIEs related to the different isotope substitutions. However, the calculated gas-phase values are found to be systematically higher than those experimentally observed in aqueous solution. On the other hand, the addition of explicit solvent molecules (up to 24 waters) in the first solvation shells of the phosphate ion substantially improves the calculated EIE, which approaches the experimental value with increasing size of the water cluster. The large effects of surrounding water molecules on the phosphate deprotonation EIE can be explained by the strong solute-solvent interactions, which result in solvent coupled vibrational modes of the phosphate ions.

Deuterium↗
PubMed2002

Ligand binding affinities from MD simulations.

Simplified free energy calculations based on force field energy estimates of ligand-receptor interactions and thermal conformational sampling have emerged as a useful tool in structure-based ligand design. Here we give an overview of the linear interaction energy (LIE) method for calculating ligand binding free energies from molecular dynamics simulations. A notable feature is that the binding energetics can be predicted by considering only the intermolecular interactions of the ligand in the associated and dissociated states. The approximations behind this approach are examined, and different parametrizations of the model are discussed. LIE-type methods appear particularly promising for computational "lead optimization". Recent applications to protein-protein interactions and ion channel blocking are also discussed.

Animals↗