New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study

Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal ``glutaminase'' (GAT) and C-terminal ``synthetase'' domain. The enzyme is identified as a potential target for anticancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site.

Making consistent contacts to graphene: effect of architecture and growth induced defects

The effects of contact architecture, graphene defect density and metal-semiconductor work function difference on the resistivity of metal-graphene contacts have been investigated. An architecture with metal on the bottom of graphene is found to yield resistivities that are lower, by a factor of four, and most consistent as compared to metal on top of graphene. Growth defects in graphene film were found to further reduce resistivity by a factor of two. Using a combination of method and metal used, the contact resistivity of graphene has been decreased by a factor of 10 to 1200. +/-. 250 Omega mu m using palladium as the contact metal. While the improved consistency is due to the metal being able to contact uncontaminated graphene in the metal on the bottom architecture, lower contact resistivities observed on defective graphene with the same metal are attributed to the increased number of modes of quantum transport in the channel.