Voltammetric Study of Some 3-Aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide Derivatives with Anti-Tumor Activities.

The electrochemical properties of twenty 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives with varying degrees of cytotoxic activity were investigated in dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. With one exception, the first reduction of these compounds was found to be reversible or quasireversible and is attributed to reduction of the N-oxide moiety to form a radical anion. The second reduction of the diazine ring was found to be irreversible. Compounds containing a nitro group on the 3-phenyl ring also exhibited a reduction process that may be attributed to that group. There was good correlation between molecular structure and reduction potential, with reduction being facilitated by an enhanced net positive charge at the electroactive site created by electron withdrawing substituents. Additionally, the reduction potential was calculated using two common basis sets, 6-31g and lanl2dz, for five of the test molecules. There was a strong correlation between the computational data and the experimental data, with the exception of the derivative containing the nitro functionality. No relationship between the experimentally measured reduction potentials and reported cytotoxic activities was evident upon comparison of the data.

MoD-QM/MM Structural Refinement Method: Characterization of Hydrogen Bonding in the Oxytricha nova G-Quadruplex.

A generalization of the Moving-Domain Quantum Mechanics/Molecular Mechanics (MoD-QM/MM) hybrid method [Gascon, J. A.; Leung, S. S. F.; Batista, E. R.; Batista, V. S. J. Chem. Theory Comput. 2006, 2, 175-186] is introduced to provide a self-consistent computational protocol for structural refinement of extended systems. The method partitions the system into molecular domains that are iteratively optimized as quantum mechanical (QM) layers embedded in their surrounding molecular environment to obtain an ab initio quality description of the geometry and the molecular electrostatic potential of the extended system composed of those constituent fragments. The resulting methodology is benchmarked as applied to model systems that allow for full QM optimization as well as through refinement of the hydrogen bonding geometry in Oxytricha nova guanine quadruplex for which several studies have been reported, including the X-ray structure and NMR data. Calculations of (1)H NMR chemical shifts based on the gauge independent atomic orbital (GIAO) method and direct comparisons with experiments show that solvated MoD-QM/MM structures, sampled from explicit solvent molecular dynamics simulations, allow for NMR simulations in much improved agreement with experimental data than models based on the X-ray structure or those optimized using classical molecular mechanics force fields.

Role of electrostatics in differential binding of RalGDS to Rap mutations E30D and K31E investigated by vibrational spectroscopy of thiocyanate probes.

The human protein Rap1A (Rap) is a member of the Ras superfamily of GTPases that binds to the downstream effector Ral guanine nucleotide dissociation stimulator (RalGDS). Although Ras and Rap have nearly identical amino acid sequences and structures along the effector binding surface, the charge reversal mutation Rap K31E has previously been shown to increase the dissociation constant of Rap-RalGDS docking to values similar to that of Ras-RalGDS docking. This indicates that the difference in charge at position 31 could provide a mechanism for Ral to distinguish two structurally similar but functionally distinct GTPases, which would be of vital importance for appropriate biological function. In this report, vibrational Stark effect spectroscopy, dissociation constant measurements, and molecular dynamics simulations were used to investigate the role that electrostatic field differences caused by the charge reversal mutation Rap K31E play in determining the binding specificity of RalGDS to Rap versus Ras. To do this, six variants of RalGDS carrying a thiocyanate electrostatic probe were docked with three Rap mutants, E30D, K31E, and E30D/K31E. The change in absorption energy of the thiocyanate probe caused by RalGDS docking to these Rap variants was then compared to that observed with wild-type Ras. Three trends emerged: the expected reversion behavior, an additive behavior of the two single mutations, and cancelation of the effects of each single mutation in the double mutant. These observations are explained with a physical model of the position of the thiocyanate probe with respect to the mutated residue based on molecular dynamics simulations.