No abstract

Optimization approaches using several global and local algorithms (genetic algorithms, direct search and implicit filtering) in the search for a global minimum are applied to optimize auxiliary basis sets for quantum chemistry ab initio calculations. We optimize mixed Poisson and density auxiliary basis sets for RI-MP2, by minimizing a suitable objective function DI. For H, B, C, N, O and F optimized auxiliary basis sets are reported for cc-pVXZ (X ¼ D, T and Q). The auxiliary basis sets optimized in this work are all even-tempered series. As results from these approaches, we never observed errors (DI/|E MP2 |) greater than 0.55 mE h per atom. In more than 90% of all cases the errors were smaller than 0.009 mE h . Moreover, these approximations affect molecular MP2 energies by less than 30 mE h per atom. In contrast to traditional attempts to optimize auxiliary basis sets, this approach is faster and more reliable.

To obtain basic information such as interaction between the water molecule and amino acids in the active site of HIV-1 Reverse Transcriptase (HIV-1 RT), ab initio molecular orbital calculations and the two-layer ONIOM method were performed. The energetic results from different methods show that the ONIOM2 (MP2/6-311G:HF/6-31G//HF/6-31G:HF/3-21G) can provide reliable results on the orientation of the water molecule in the HIV-1 RT active site. The interaction between the water molecule and Asp186 was found to be the most preferable. The obtained results from ONIOM2 calculations indicated that the active site model system included six amino acid residues (Asp186, Asp185, Met184, Tyr183, Leu187, and Tyr188) leading a preferable representation of the environment surrounding the water molecule in the more realistic model. The water molecule presented in the active site tends to form H-bonding with Asp186, Tyr183, and Tyr188 as indicated by the distances of O4-H2 = 1.91 A, O3-H7 = 2.36 A, and O3-H17 = 1.73 A, respectively. The stability of this complex system brings to the foundation of the estimated binding energy approximately -15.8 kcal/mol or -8.1 kcal/mol which is more stabilized relative to the smallest model complex. These observations revealed that the water molecule forms both a hydrogen bond donor and a hydrogen bond acceptor in the cavity and plays an important role in the specific conformation of the active site of HIV-1 RT. The H-bonding is a rather strong interaction; thus, the water might induce the conformation of the active site to fit the catalysis process and helpfully attract dNTP to elongate the viral DNA in the replication process of this enzyme.

Tryptamine (T) and several T derivatives (Ts) inhibit in a voltage-dependent manner the NMDA receptor (NR). This effect is influenced by substituents at various positions, but has not yet been subjected to a detailed SAR study. Here, 64 Ts have been tested as inhibitors of [3H]MK-801 binding to NRs on rat brain membranes. For comparison, they were also tested as inhibitors of [3H]8-OHDPAT binding to 5-HT1A and of [3H]ketanserin binding to 5-HT2A receptors. Since most of these Ts have not been tested before at any of these receptors, we start with a review of the effects of Ts on 5-HT1A and 5-HT2A binding sites. NRs were inhibited with IC50s from 2 to 7 μM by Ts with alkyl or halogen at positions 2, 5, and/or 7. Inhibition by some Ts was attenuated more than 10-fold by 30 μM spermine. The most potent inhibitors at 5-HT1A receptors were 5-carboxamido-T (IC50 0.00015 μM) and serotonin (0.0016 μM), at 5-HT2A receptors 2-Me-4,7-Cl2-T (1.2 μM) and 2,7-Me2-4-Cl-T (2.0 μM). Fujita-Ban modified Free-Wilson analyses pointed to the individual significance of particular substituents. Also QSARs based on molecular operating environment descriptors resulted in sound correlations at all 4 targets. No similarities between the NR and 5-HT receptors could be found. At the NR, only L-Trp-NH2 bound 10 times better than at both 5-HT receptors studied. L-Trp-NH2 may be a structural lead to endogenous non-competitive NR antagonists.

A novel, simple and precise electrochemical biosensor, was developed for measuring mevalonic acid (MA) concentration, which is thought to be a good indicator of HMG-CoA reductase activity. This sensor is based on noncovalent-linking NAD+/MWNTs nanocomposite coated on a screen-printed electrode (SPE). The resulting biosensor exhibited excellent electrocatalytic activity, fast response and good stability to MA. At the NAD+/MWNTs-modified SPE, the current is linear with the concentration of MA being within a concentration range from 18.1 to 145 μM with a limit of detection down to 4.25 μM (S/N = 3), and the sensor exhibited a sensitivity of 92.2 μA/mM.