Ab initio computational modeling of long loops in G-protein coupled receptors

A newly developed approach for predicting the structure of segments that connect known elements of secondary structure in proteins has been applied to some of the longer loops in the G-protein coupled receptors (GPCRs) rhodopsin and the dopamine receptor D2R. The algorithm uses Monte Carlo (MC) simulation in a temperature annealing protocol combined with a scaled collective variables (SCV) technique to search conformation space for loop structures that could belong to the native ensemble. Except for rhodopsin, structural information is only available for the transmembrane helices (TMHs), and therefore the usual approach of finding a single conformation of lowest energy has to be abandoned. Instead the MC search aims to find the ensemble located at the absolute minimum free energy, i.e., the native ensemble. It is assumed that structures in the native ensemble can be found by an MC search starting from any conformation in the native funnel. The hypothesis is that native structures are trapped in this part of conformational space because of the high-energy barriers that surround the native funnel. In this work it is shown that the crystal structure of the second extracellular loop (e2) of rhodopsin is a member of this loop’s native ensemble. In contrast, the crystal structure of the third intracellular loop is quite different in the different crystal structures that have been reported. Our calculations indicate, that of three crystal structures examined, two show features characteristic of native ensembles while the other one does not. Finally the protocol is used to calculate the structure of the e2 loop in D2R. Here, the crystal structure is not known, but it is shown that several side chains that are involved in interaction with a class of substituted benzamides assume conformations that point into the active site. Thus, they are poised to interact with the incoming ligand.     

Revisiting the structure and dynamics of hydrated Cd2+ in aqueous solutions: Insights from the RI-SCS-MP2/MM molecular dynamics simulation

The spin component scale MP2/molecular mechanics molecular dynamics simulation investigated the hydration shell formation and hydrated Cd²⁺ dynamics in the water environment. At the first hydration shell, six water molecules with 2.27 Å for the average distance between water and Cd²⁺. Dynamical properties were analyzed by computing the water molecule's mean residence time (MRT) in its first and second hydration shells. The MRT of each shell was determined to be 31.8 and 1.92 ps, suggesting the strong influence of Cd²⁺ in the first hydration shell. The second shell was labile, with an average number of water molecules being 18. Despite the strong interaction between Cd²⁺ and water molecules in the first shell, the influence of ions in the second hydration shell remained weak.     

Fast topological analysis of 2D and 3D grids of data: application to the atoms in molecule (AIM) and the electron localization function (ELF)

The topological analysis of grids of data is used for determination of surfaces or volumes around maxima. The volumes are then related to chemical information such as atoms or bonds, and can be used for integration of local properties such as electronic population. The problem of global connectivity is reversed into the question of local connectivity yielding a linear scaling partition algorithm. Two packages are developed for a very fast analysis and partition of 2D or 3D grids of data, applications being made to C2H2, C2H4, C6H6, H2CO, and H2CS molecules using the Atoms in Molecule (AIM) or Electron Localization Function (ELF).