Mapping the intramolecular signal propagation pathways in protein using Bayesian change point analysis of atomic motions.

We propose to use change points of atomic positions in the molecular dynamics trajectory as indicators of the propagating signals in protein. We designate these changes as signals because they can propagate within the molecule in the form of "perturbation wave", transmit energy or information between different parts of protein, and serve as allosteric signals. We found that change points can distinguish between thermal fluctuations of atoms (noise) and signals in a protein despite the differences in the motility of amino acid residues.

Graph-theoretical comparison of protein surfaces reveals potential determinants of cross-reactivity and the molecular mimicry.

Different proteins, even without sequence similarity, still can contain similar surface regions involved in protein-protein interactions with common target. These regions can serve as structural determinants of cross-reactivity and molecular mimicry. Molecular mimicry, defined as the process in which structural properties of one molecule are simulated by the dissimilar molecules, is implicated in several biologically important processes, including autoimmune and allergic reactions, binding of some ligands to common receptor, and interactions in cell signaling.

Mutagenesis studies toward understanding allostery in thrombin.

The binding of thrombomodulin (TM) to exosite-1 and the binding of Na(+) to 225-loop allosterically modulate the catalytic activity and substrate specificity of thrombin. To determine whether the conformation of these two cofactor-binding loops are energetically linked to each other and to the active site, we rationally designed two thrombin mutants in which either the 70-80 loop of exosite-1 or the 225-loop of the Na(+)-binding site was stabilized by an engineered disulfide bond. This was possible by replacing two residues, Arg-67 and Ile-82, in the first mutant and two residues, Glu-217 and Lys-224, in the second mutant with Cys residues.

Possible mechanisms contributing to oxidative inactivation of activated protein C: molecular dynamics study.

Activated protein C (APC) is a serine protease, an effector enzyme of the natural anticoagulant pathway. APC is approved for treatment of severe sepsis characterized by the increased concentrations of H(2)O(2) and hypochlorite. We found that treatment of APC with these oxidants markedly inhibits the cleavage of the APC-specific chromogenic substrate, suggesting that oxidants can induce changes in the structure of the active site of APC.

Thrombomodulin-mediated catabolism of protein C by pleural mesothelial and vascular endothelial cells.

Pleural mesothelial and vascular endothelial cells express protein C (PC) pathway components including thrombomodulin (TM) and endothelial protein C receptor (EPCR) and activate PC by the thrombin-TM dependent mechanism. We used these cells as model systems to identify molecules involved in endocytosis and degradation of PC. We find that mesothelial and endothelial cells can bind, internalize and degrade PC.