Biomedical subjects

Alexei A Podtelezhnikov

Publications and source records attributed to Alexei A Podtelezhnikov.

3 recordsLinked to original sources

PubMed2007

Learning about protein hydrogen bonding by minimizing contrastive divergence.

Defining the strength and geometry of hydrogen bonds in protein structures has been a challenging task since early days of structural biology. In this article, we apply a novel statistical machine learning technique, known as contrastive divergence, to efficiently estimate both the hydrogen bond strength and the geometric characteristics of strong interpeptide backbone hydrogen bonds, from a dataset of structures representing a variety of different protein folds. Despite the simplifying assumptions of the interatomic energy terms used, we determine the strength of these hydrogen bonds to be between 1.1 and 1.5 kcal/mol, in good agreement with earlier experimental estimates. The geometry of these strong backbone hydrogen bonds features an almost linear arrangement of all four atoms involved in hydrogen bond formation. We estimate that about a quarter of all hydrogen bond donors and acceptors participate in these strong interpeptide hydrogen bonds.

Amino Acids↗

PubMed2005

Exhaustive Metropolis Monte Carlo sampling and analysis of polyalanine conformations adopted under the influence of hydrogen bonds.

We propose a novel Metropolis Monte Carlo procedure for protein modeling and analyze the influence of hydrogen bonding on the distribution of polyalanine conformations. We use an atomistic model of the polyalanine chain with rigid and planar polypeptide bonds, and elastic alpha carbon valence geometry. We adopt a simplified energy function in which only hard-sphere repulsion and hydrogen bonding interactions between the atoms are considered. Our Metropolis Monte Carlo procedure utilizes local crankshaft moves and is combined with parallel tempering to exhaustively sample the conformations of 16-mer polyalanine. We confirm that Flory's isolated-pair hypothesis (the steric independence between the dihedral angles of individual amino acids) does not hold true in long polypeptide chains. In addition to 3(10)- and alpha-helices, we identify a kink stabilized by 2 hydrogen bonds with a shared acceptor as a common structural motif. Varying the strength of hydrogen bonds, we induce the helix-coil transition in the model polypeptide chain. We compare the propensities for various hydrogen bonding patterns and determine the degree of cooperativity of hydrogen bond formation in terms of the Hill coefficient. The observed helix-coil transition is also quantified according to Zimm-Bragg theory.

Hydrogen Bonding↗

PubMed2003

Modeling HIV-1 integrase complexes based on their hydrodynamic properties.

We present a model structure of a candidate tetramer for HIV-1 integrase. The model was built in three steps using data from fluorescence anisotropy, structures of the individual integrase domains, cross-linking data, and other biochemical data. First, the structure of the full-length integrase monomer was modeled using the individual domain structures and the hydrodynamic properties of the full-length protein that were recently measured by fluorescence depolarization. We calculated the rotational correlation times for different arrangements of three integrase domains, revealing that only structures with close proximity among the domains satisfied the experimental data. The orientations of the domains were constrained by iterative tests against the data on cross-linking and footprinting in integrase-DNA complexes. Second, the structure of an integrase dimer was obtained by joining the model monomers in accordance with the available dimeric crystal structures of the catalytic core. The hydrodynamic properties of the dimer were in agreement with the experimental values. Third, the active sites of the two model dimers were placed in agreement with the spacing between the sites of integration on target DNA as well as the integrase-DNA cross-linking data, resulting in twofold symmetry of a tetrameric complex. The model is consistent with the experimental data indicating that the F185K substitution, which is found in the model at a tetramerization interface, selectively disrupts correct complex formation in vitro and HIV replication in vivo. Our model of the integrase tetramer bound to DNA may help to design anti-integrase inhibitors.

Base Sequence↗