Biomedical subjects

Maria Kurnikova

Publications and source records attributed to Maria Kurnikova.

4 recordsLinked to original sources

PubMed2006

Structure and energetics of channel-forming protein-polysaccharide complexes inferred via computational statistical thermodynamics.

The ion channel protein alpha-hemolysin (alphaHL) forms supramolecular complexes with the polysaccharide beta-cyclodextrin (betaCD). This system has potential uses in nanoscale device engineering. It has been found recently that betaCD formed longer- or shorter-lived complexes with some engineered alphaHL mutants then with a wild type protein (Gu et al. J. Gen. Physiol. 2001, 118, 481-493). However, how changes in the protein sequence affect complex lifetime was not completely understood in part due to the lack of knowledge of structures of these metastable complexes. In this paper, we present an extensive molecular modeling study of the betaCD-alphaHL and selected mutant complexes to gain insights into the betaCD-alphaHL interaction mechanisms and to predict possible structures and energetics of the complexes. Thermodynamic integration (TI) and umbrella sampling (US) techniques (with the weighted histogram analysis method (WHAM)) were used to calculate the relative binding affinities of the complexes formed with the wild type alphaHL and the M113N, M113E, M113A, and M113V mutants. Our results are in excellent agreement with experiment. While betaCD-M113N and betaCD-M113A complexes were stable in the configuration of the wild type complex, the equilibrium configuration of the betaCD-M113V and betaCD-M113E complexes was significantly different. In these cases, TI alone was insufficient to accurately calculate the corresponding free energy differences. By utilizing a TI/US combination in a novel manner, we were able to accurately calculate free energy changes in these flexible systems. The betaCD-M113A and betaCD-M113E complexes, which exhibited shorter lifetimes than other complexes in an experiment, in simulations exhibited greater flexibility and higher water solvation of the betaCD adapter. MD simulations of the betaCD-M113N complex with betaCD in a downward orientation were also performed.

Bacterial Proteins↗

PubMed2005

Protein flexibility using constraints from molecular dynamics simulations.

Proteins are held together in the native state by hydrophobic interactions, hydrogen bonds and interactions with the surrounding water, whose strength as well as spatial and temporal distribution affects protein flexibility and hence function. We study these effects using 10 ns molecular dynamics simulations of pure water and of two proteins, the glutamate receptor ligand binding domain and barnase. We find that most of the noncovalent interactions flicker on and off over typically nanoseconds, and so we can obtain good statistics from the molecular dynamics simulations. Based on this information, a topological network of rigid bonds corresponding to a protein structure with covalent and noncovalent bonds is constructed, with account being taken of the influence of the flickering hydrogen bonds. We define the duty cycle for the noncovalent interactions as the percentage of time a given interaction is present, which we use as an input to investigate flexibility/rigidity patterns, in the algorithm FIRST which constructs and analyses topological networks.

Algorithms↗

PubMed2005

On the binding determinants of the glutamate agonist with the glutamate receptor ligand binding domain.

Ionotropic glutamate receptors (GluRs) are ligand-gated membrane channel proteins found in the central neural system that mediate a fast excitatory response of neurons. In this paper, we report theoretical analysis of the ligand-protein interactions in the binding pocket of the S1S2 (ligand binding) domain of the GluR2 receptor in the closed conformation. By utilizing several theoretical methods ranging from continuum electrostatics to all-atom molecular dynamics simulations and quantum chemical calculations, we were able to characterize in detail glutamate agonist binding to the wild-type and E705D mutant proteins. A theoretical model of the protein-ligand interactions is validated via direct comparison of theoretical and Fourier transform infrared spectroscopy (FTIR) measured frequency shifts of the ligand's carboxylate group vibrations [Jayaraman et al. (2000) Biochemistry 39, 8693-8697; Cheng et al. (2002) Biochemistry 41, 1602-1608]. A detailed picture of the interactions in the binding site is inferred by analyzing contributions to vibrational frequencies produced by protein residues forming the ligand-binding pocket. The role of mobility and hydrogen-bonding network of water in the ligand-binding pocket and the contribution of protein residues exposed in the binding pocket to the binding and selectivity of the ligand are discussed. It is demonstrated that the molecular surface of the protein in the ligand-free state has mainly positive electrostatic potential attractive to the negatively charged ligand, and the potential produced by the protein in the ligand-binding pocket in the closed state is complementary to the distribution of the electrostatic potential produced by the ligand itself. Such charge complementarity ensures specificity to the unique charge distribution of the ligand.

Algorithms↗

PubMed2004

Accurate theoretical prediction of vibrational frequencies in an inhomogeneous dynamic environment: a case study of a glutamate molecule in water solution and in a protein-bound form.

We propose a hierarchical approach to model vibrational frequencies of a ligand in a strongly fluctuating inhomogeneous environment such as a liquid solution or when bound to a macromolecule, e.g., a protein. Vibrational frequencies typically measured experimentally are ensemble averaged quantities which result (in part) from the influence of the strongly fluctuating solvent. Solvent fluctuations can be sampled effectively by a classical molecular simulation, which in our model serves as the first, low level of the hierarchy. At the second high level of the hierarchy a small subset of system coordinates is used to construct a patch of the potential surface (ab initio) relevant to the vibration in question. This subset of coordinates is under the influence of an instantaneous external force exerted by the environment. The force is calculated at the lower level of the hierarchy. The proposed methodology is applied to model vibrational frequencies of a glutamate in water and when bound to the Glutamate receptor protein and its mutant. Our results are in close agreement with the experimental values and frequency shifts measured by the Jayaraman group by the Fourier transform infrared spectroscopy [Q. Cheng et al., Biochem. 41, 1602 (2002)]. Our methodology proved useful in successfully reproducing vibrational frequencies of a ligand in such a soft, flexible, and strongly inhomogeneous protein as the Glutamate receptor.

Computer Simulation↗