Modeling intermolecular interactions using the transferable atom equivalent method

Within the framework of computational chemistry, there are two broad areas of significance: molecular mechanics and electronic structure theory. These areas differ in theoretical complexity, and applicability. The molecular mechanics model chemistry, the least complex of the two areas, can be applied to large systems yielding low quality results. Using electronic structure theory, it is possible to obtain high quality results but on much smaller systems. The Transferable Atom Equivalent (TAE) method was born out of the need to calculate high quality electronic energies and properties quickly and efficiently. Since the TAE method has its basis in the theory of Atoms in Molecules and uses high quality ab initio wavefunctions, it has a unique combination of speed and quality. Prior to this work, there were some hurdles to overcome to allow the TAE method to be general applicable. First, in order to accurately model a system, all of the atoms within that systems must be represented by a TAE within the TAE library. When an un-parameterized atom was encountered, there was no efficient method in place to add that atom to the TAE library. Section 3.1 and Appendix 1 describe a method of efficiently adding a new atomtype to the TAE library. Second, there must be a fast and robust method of reconstructing molecular systems. Section 3.2 describes a method for reconstructing molecular systems that fast and efficient. Finally there must be a reliable method in place that adjust a TAE properties to a new environment. Section 3.3 describes a method of using topological properties to adjust TAE electronic properties to a new environment. These problems are discussed and many of their solutions are presented in this work.; The TAE method was applied to two problems of novel interest. The first problem involves finding a way of approximating Molecular Electrostatic Potentials (MEPs) that are fast, accurate and conformationally sensitive. Current procedures for approximating MEPS have some of the combination of the above qualities, but not all of them. In Chapter 4, the TAE multipoles were used in a multi-centered multipole expansion (TAE-MA) to calculate the MEP on molecular van der Waals surfaces. It was found that the TAE-MA method was able recover the conformational sensitivity of the MEPs when compared to analytically derived MEPS. In another investigation, the TAE descriptor fields were used as part of a new kind of 3-D QSAR/QSPR Field analysis known as Electron Density-Derived Field Analysis (EDDFA). EDDFA is an application of the well-known Comparative Molecular Field Analysis (CoMFA). Since EDDFA used electron density-derived properties, it has an added advantage over CoMFA. The property fields available are chemically relevant and correlated with potential binding modes. Chapter 5 details the use of EDDFA and CoMFA acetylcholinesterase, Law and Malaria datasets.