Optimization of parameters for semiempirical methods VI: more modifications to the NDDO approximations and re-optimization of parameters

Modern semiempirical methods are of sufficient accuracy when used in the modeling of molecules of the same type as used as reference data in the parameterization. Outside that subset, however, there is an abundance of evidence that these methods are of very limited utility. In an attempt to expand the range of applicability, a new method called PM7 has been developed. PM7 was parameterized using experimental and high-level ab initio reference data, augmented by a new type of reference data intended to better define the structure of parameter space. The resulting method was tested by modeling crystal structures and heats of formation of solids. Two changes were made to the set of approximations: a modification was made to improve the description of noncovalent interactions, and two minor errors in the NDDO formalism were rectified. Average unsigned errors (AUEs) in geometry and ΔH(f) for PM7 were reduced relative to PM6; for simple gas-phase organic systems, the AUE in bond lengths decreased by about 5 % and the AUE in ΔH(f) decreased by about 10 %; for organic solids, the AUE in ΔH(f) dropped by 60 % and the reduction was 33.3 % for geometries. A two-step process (PM7-TS) for calculating the heights of activation barriers has been developed. Using PM7-TS, the AUE in the barrier heights for simple organic reactions was decreased from values of 12.6 kcal/mol(-1) in PM6 and 10.8 kcal/mol(-1) in PM7 to 3.8 kcal/mol(-1). The origins of the errors in NDDO methods have been examined, and were found to be attributable to inadequate and inaccurate reference data. This conclusion provides insight into how these methods can be improved. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00894-012-1667-x) contains supplementary material, which is available to authorized users

A theoretical study of TPA-like tumour promotors and inositol polyphosphates

In this thesis, the structures and selected properties of TPA-like tumour promoters and of Myo-inositol polyphosphates are calculated and compared with their promoting and calcium releasing activities respectively. Three different levels of theory are used in the calculations, namely ab initio, semi empirical and molecular mechanics, though the majority of the calculations are performed using the MNDO derived semi-empirical methods implemented in MOPAC. A detailed description of the phorbol ester / DAG binding site is obtained from the structure / activity relationships derived for the tumour promoters and molecular dynamics simulations of the phorbol ester, TPA, in a lipid bilayer is carried out to investigate the position of the binding groups in relation to the surface of the bilayer. In order to carry out this simulation, a method (HYDRO) has been developed to produce close packed heterogeneous bilayers in which the headgroups of the components lie in random orientations. Thus the simulations are more realistic than calculations in which the lipids are placed in a regular array and interstitial spaces due to the difference in surface area of the bilayer components are kept to a minimum. The effects of the number and position of phosphate groups on the ring conformations of myo -inositol phosphates and the connection between this and calcium releasing activity are studied in chapter 5. As the molecules are particularly flexible with a large number of potential local minima, phosphate groups have been added sequentially to keep the required number of starting points as low as possible and rotation of phosphate hydroxyls has been ignored. The heats of formation, calculated with the different semi-empirical parametrisations, differ considerably, so the final calculations chapter compares energies and selected properties calculated for model organics phosphates using different methods and theory. The results using the new parametrisation, PM3, are compared with those of the earlier AMI for both the phorbol systems and the inositol phosphates to test its suitability

Pyridazinediones and amino acid receptors: theoretical studies, design, synthesis, and evaluation of novel analogues

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands

Pyridazinediones and amino acid receptors: theoretical studies, design, synthesis, and evaluation of novel analogues

http://www.pharmacol.usyd.edu.au/thesis This thesis is primarily concerned with a class of chemical compounds known as pyridazinediones, being 6-membered aromatic rings containing two adjacent nitrogen atoms (pyridazine), doubly substituted with oxygen. In particular, the work focuses on pyridazine-3,6-diones, derivatives of maleic hydrazide (1). Understanding of the chemistry of these compounds is extended, using theoretical and synthetic techniques. This thesis is also concerned with two very important classes of receptors which bind amino acids in the brain: firstly, the inhibitory GABA receptor, which binds g-aminobutyric acid (GABA) (2) in vivo, and for which muscimol (3) is an agonist of the GABAA subclass; secondly, Excitatory Amino Acid (EAA) receptors, which bind glutamate (4) in vivo, and in particular the AMPA subclass, for which (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) (5) is an agonist. The connection between pyridazinediones and amino acid receptors is the design, synthesis, and evaluation of structures based on pyridazinediones as potential GABA and EAA receptor ligands. Techniques of theoretical chemistry, molecular modelling, synthetic chemistry, and in vitro pharmacology are used to explore pyridazine-3,6-dione derivatives as ligands

Application of molecular simulation techniques to the design of nanosystems

Nanotechnology is a multidisciplinary branch of science and technology that involves a widerange of different fields such as chemistry, materials science, physics or chemical engineeringwhose goal is the production of new functional materials and devicesthrough the control of their organization at the atomic and molecular scale.Nanotechnology has jumped from research laboratories to our daily life and today all theprogresses made in this field have been translated into direct applications in different fields being electronics and computer science and biomedicine, where the most striking advances have beendone.What differences nanotechnology from traditional chemistry and physics can be summarized inthree points: (i) Analysis and control of the matterat the atomic and molecular level focusing in individual atoms; (ii) the appearance of novel physical properties because of the nanoscopicdimensions; (iii) the possibility of generating new complex functional systems with novelproperties.Modeling and theory are becoming vital to designing and improving nanodevices. The intrinsicnature of nano and supramolecular scale that involves tens, hundreds and thousands of atomsmakes computational chemistry the perfect ally to design new devices and predict their properties. Computational chemistry provides the perfect tools to describe the electronic structureand the dynamic behavior, as well as the properties derived from them, through quantummechanics and classical mechanics formalisms.The suitability of such techniques in the design and improvement of nanodevices as well as theprediction of their properties is clearly proven throughout the four blocks in which this thesis isdivided:· Nanotubes based on natural peptide sequencesNanotubes have gained extensive interest because of their applicability in different fieldsranging from medicine to electronics. Among nanotubes, those based on natural peptidesequences taken from some natural proteins with a tubular or fibrillar motif are gaining abroad attention because of their high biocompatibility, the possibility of adding functionalitiesby tuning them and their potentiality to self-assemble. The enhancement of the ability to retain the tubular geometry of such structures can be achieved by substituting targeted amino acids located in the more flexible parts of the nanoconstruct by synthetic amino acids withlow conformational flexibility providing a larger rigidity to the overall structure.· Dendronized polymersDendronized polymers are a specific kind of macromolecule structure that consists of a linearpolymeric backbone where dendritic units are attached regularly leading to a highly branchedthree-dimensional architecture. This fact provides dendronized polymers the peculiarity of the coexistence within the same macromolecule of three topological regions: (i) the internalbackbone; (ii) the dendron region around the backbone and (iii) the external surface. Thesemolecules have a wide range of applications in different fields such as biomedical engineering, host-guest chemistry or catalysis.· Theoretical study of ð-conjugated systemsConducting polymers are polymers bearing a characteristic polyconjugated nature which makethem electronic conductors. In particular thiophene-based conducting polymers have been widely studied because of their electric and nonlinear optical properties, excellent environmentalstability and relatively low cost of production. Due to the crucial role played by the electronicstructure of these systems in their relevant properties, a good knowledge of it is a key factor todesign and improve new conducting polymers. To achieve this goal QM calculations suitperfectly to get accurate estimates of such properties.· Molecular actuators and sensors based on conducting polymersBoth experimental and computational research in nanoactuators and nanosensors are widelyreported in the literature. Among them, those based in conducting polymers are flourishingbecause of their great transport properties, electrical conductivity or rate of energy migrationwhich provide amplified sensitivity in nanosensors and a rapid response in nanoactuators. In thissense electron-rich thiophene-based oligomers and polymers combined with versatilecalix[4]arenes units are presented in the present thesis. Calix[4]arenes are synthetic macrocyclic molecules consisting of four phenol or anisole rings connected via methylene bridges that canhost different guest molecules leading to conformational rearrangement of the whole device making it useful to be employed as a sensor or actuator

Theoretical studies of steroid hormones and related compounds

A theoretical study of steroidal inhibitors of the enzymes Glucose-6-Phosphate Dehydrogenase and Aromatase is presented. Both enzyme systems are of interest in the study of cancer, the latter being the final step in the biosynthesis of oestrogens which are involved in certain types of breast cancer. Two levels of theory are employed in the study, namely, Ab Initio and Semi Empirical methods. Structures and charges have been calculated using the MOPAC and GAUSSIAN programs and these have been used to model the efficacy of various inhibitors. The major tool in comparing these steroids has been the molecular electrostatic potential (MEP). Maps of the MEP and an analysis of the similarity between the MEP s of different molecules have led both to a method of assessing the activities of steroids as enzyme inhibitors and requirements for the electronic structure of the steroid binding sites within these enzymes. A molecular graphics display program has been developed to facilitate this work. It has been designed to make full use of the facilities available. The quality of the resulting display has improved greatly on what was previously available and has been of value in studies of large molecular systems. The program is written in VAX FORTRAN and uses the Graphics Kernel System (GKS) to produce graphical output and should be reasonably easy to transfer to other systems. Finally, to determine whether PM3 really is a significant advance on AM1, a comparison of the two semi empirical methods is presented. The calculated properties of steroid hormones are compared to those of both Ab Initio calculations and experimental determinations, allowing the quality of the semi empirical predictions to be assessed

Prediction of Peptide Binding to Major Histocompatibility II Receptors with Molecular Mechanics and Semi-Empirical Quantum Mechanics Methods

Methods for prediction of the binding of peptides to major histocompatibility complex (MHC) II receptors are examined, using literature values of IC50 as a benchmark. Two sets of IC50 data for closely structurally related peptides based on hen egg lysozyme (HEL) and myelin basic protein (MBP) are reported first. This shows that methods based on both molecular mechanics and semi-empirical quantum mechanics can predict binding with good-to-reasonable accuracy, as long as a suitable method for estimation of solvation effects is included. A more diverse set of 22 peptides bound to HLA-DR1 provides a tougher test of such methods, especially since no crystal structure is available for these peptide-MHC complexes. We therefore use sequence based methods such as SYFPEITHI and SVMHC to generate possible binding poses, using a consensus approach to determine the most likely anchor residues, which are then mapped onto the crystal structure of an unrelated peptide bound to the same receptor. This analysis shows that the MM/GBVI method performs particularly well, as does the AMBER94 forcefield with Born solvation model. Indeed, MM/GBVI can be used as an alternative to sequence based methods in generating binding poses, leading to still better accuracy

Computational Techniques

This chapter introduces fundamental computational approaches and ideas to energy materials. These can be divided into two main streams: one dealing with the motion of atoms or ions described at a simplified level of theory and another focusing on electrons. The modeling framework, which covers both streams, is outlined. The atomistic simulation techniques discussed in the chapter are concerned with describing the energy landscape of individual atoms or ions, where classical mechanics can be usefully employed as the first successful approximation. Multiscale approaches could be the method of choice if one is interested in large molecules, inhomogeneous solids, complex environments or geometrical arrangements, systems that are far away from equilibrium or have particularly long evolution times. One of the principal objectives of atomistic simulations is to derive an accurate and coherent approach to the prediction of defect structure, energetics and properties. Two of the most widely employed methods are outlined. This edition first published 2013 © 2013 John Wiley & Sons, Ltd