Correlations between MO Eigenvectors and the Thermochemistry of Simple Organic Molecules, Related to Empirical Bond Additivity Schemes

A bondingness term is further developed to aid in heat of formation (ΔfHº) calculations for C, N, O and S containing molecules. Bondingness originated from qualitative investigations into the antibonding effect in the occupied MOs of ethane. Previous work used a single parameter for bondingness to calculate ΔfHº in an alkane homologous series using an additivity scheme. This work modifies the bondingness algorithm and uses the term to parameterise a test group of 345 molecules consisting of 17 subgroups that include alkanes, alkenes, alkynes, alcohols, ethers, aldehydes, ketones, carboxylic acids, esters, amines, amides, diazenes, nitriles, nitroalkanes, nitrates, thiols and benzenoids. Comparing experimental with calculated ΔfHº values, a standard deviation for the residuals of 6.3 kJ mol 1 can be achieved using bondingness with a simple steric repulsion term (SSR) in a bond additivity scheme, and a standard deviation of 5.2 kJ mol 1 can be achieved using a Lennard-Jones potential. The method is compared with the group method of Pedley, which for a slightly smaller set of 338 molecules, a subset of the test set of 345 molecules, gives a standard deviation of 7.0 kJ mol 1. Bondingness, along with SSR or a Lennard-Jones potential, is parameterised in the lowest level of ab initio (HF-SCF) or semiempirical quantum chemical calculations. It therefore may be useful in determining the ΔfHº values for the largest molecules that are amenable to quantum chemical calculation. As part of our analysis we calculated the difference between the lowest energy conformer and the average energy of a mixture populated with higher energy conformers. This is the difference between the experimental ΔfHº value and the ΔfHº calculated for a single conformer. Example calculations which we have followed are given by Dale and Eliel et al.. Dale calculates the energy difference for molecules as large as hexane using relative energies based on the number of 1,4 gauche interactions. We have updated these values with constant increments ascertained by Klauda et al. as well as ab initio MP2 cc-pVDZ relative energies and have included calculations for heptane and octane

Structure-Function Prediction of Insect Odorant Binding Proteins

This study concerns the application of bioinformatic tools for the elucidation of the biological function of insect general odorant and pheromone binding proteins (GOBPs / PBPs). These proteins are thought to function as transporters of volatile odorant molecules to olfactory receptors (ORs) situated in olfactory receptor neurons (ORNs) in insect antennae. Activation of ORNs by the odorant molecules gives rise to action potentials resulting in spatially defined patterns of glomerular activity in the brain, odour discrimination and concomitant behavioural response of the insect. The extent to which OBPs are critical for olfactory discrimination remains unclear. Numerous hypotheses have been postulated regarding the ability of OBPs to discriminate specific odorants and/or pheromones as well as their playing a role in the activation of odorant-responsive chemosensory neurons, in functioning as selective filters in odour recognition or participating in signal termination by inactivating odorant molecules. In silico binding studies of ligands and pheromones on OBPs derived from crystallographic studies or de novo homology modelling have been conducted primarily by docking and molecular dynamic (MD) simulations. It is shown that results obtained from such studies can provide useful insights and testable hypotheses with regard to the biochemical function of OBPs. Docking and MD simulations corroborate experimental evidence that the B. mori general odorant binding protein (BmorGOBP2) has considerably higher affinity than the B. mori pheromone binding protein (BmorPBPI) for the pheromonal components bombykol and bombykal and predict that this is also true for the modelled M. sexta proteins (MsexGOBP2 and MsexPBP1). In addition, steered molecular dynamics (SMD) simulations predict ligand entry and exit pathways into and out of BmorGOBP2. In addition, docking and molecular dynamics (MD) simulations with the highly homologous odorant binding proteins from A. gambiae (AgamOBP1), A. aegypti (AaegOBP1) and C. quinquefasciatus (CguiOBP1) provide evidence of differential capacity of these proteins to select ligands with specific structural characteristics

Computational approaches to fragment based screening

Polarization is an often - neglected term in molecular modelling, and this is particularly the case in docking. However, the growing interest in fragment - based drug design, coupled with the small size of fragments that makes them amenable to quantum mechanical treatment, has created new opportunities for including polarization, anisotropic electrostatics and realistic repulsion potentials in docking. We have shown that polarization implemented as induced charges can offer in the region of a 10-15% improvement in native docking results, as judged by the percentage of poses within a rather tight threshold of 0.5 or 1.0 Å, where accurate prediction of binding interactions, are more likely. This is a significant improvement given the quality of current commercial docking programs (such as Glide use d here). This improvement is most apparent when the correct pose is known a priori, so that the extent of polarization is correctly modelled, and scoring is based on force - fields that do not scale the electrostatics. The introduction of specific active - sit e water molecules was shown to have a far greater effect than the polarization, probably because of the introduction of 3 additional full charges, rather than introduction of smaller charge perturbations. With active site waters , polarization is more likely to improve the docking when the water molecule is carefully orientated using quantum mechanical/molecular mechanics (QM/MM) methods. The placement of such water molecules is a matter of great current interest; we have shown that the water molecule can be placed with some degree of reliability simply by docking with the ligand present, provided that the water makes good hydrogen bonding interactions (these are the very conditions under which it is desirable to include the specific active-site water). Anisotropic electrostatics and exponential repulsion for rigid fragments was investigated using Orient and compared to QM/MM methods, all methods merited further research. The general hierarchy is that native docking using Glide (with polarization)> QM/MM (with MM polarization)> Orient-based methods. Thus, we expanded the Glide (with polarization) dataset to include more realistic crossdocking experiments on over 5000 structures. RMSD analysis resulted in many examples of clear improvement for including polarization