One-half of my research effort is devoted to the preparation and study of organic transient species in the gas phase with ultraviolet photoelectron spectroscopy (PES). Synthesis of suitable organic precursors is a key component of this work. When combined with quantum-chemical ab-initio and DFT calculations - also a key component of our research - with Gaussian 09 that is available as a SHARCnet resource, PES provides a method for ordering the energies of molecular orbitals and yields fundamental information about the geometries and the nature of the bonding in stable and transient short-lived molecules. This information is provided by no other technique.
The remainder of my research effort involves computational studies on reaction mechanisms and reaction intermediates. Our goals are, (a) to determine preferred pathways, characterize transition states and intermediates, (b) predict the course of reactions, and (c) gain new insights into the bonding of reaction intermediates - carbocations, carbanions, carbenes, and radicals - using QTAIM-DI-VISAB analyses we developed recently. We plan to continue our QTAIM studies on the molecular structure/bonding of so-called nonclassical carbocations by calculating localization and delocalization indices at post-HF levels with our new program LIDI-CALC. One of our major goals is to rewrite the textbooks on the molecular structure/bonding of so-called non-classical carbocations (see list of publications for a series of papers published to this point). In our view QTAIM-DI-VISAB will be the method of choice for unambiguously characterizing the bonding between pairs of atoms in transient intermediates and stable molecules.
One biological system of special interest is the amyloid precursor protein (APP) which is a large ubiquitous protein found in many tissues and in synapses of neurons. It is variable in makeup and contains between 365 to 770 amino acids which possess many metal binding groups. APP undergoes extensive post-translational modification by proteases: for example, cleavage by g-secretase generates the beta amyloid fragment (Ab) associated with development of Alzheimer’s disease and other forms of dementia. Ab is a peptide of 39-42 amino acids.
Copper, often as Cu(II), has been implicated in the build-up of and suppression of Ab fibrils by binding to APP and Ab. Cu(I), with different bond strengths and coordination with different ligand groups, should also be considered and assessed. In fact, Cu-metallo enzymes containing Cu(I) and Cu(II) are wide spread in the biological domain and serve many functions. Numerous and often contradicting scenarios have been proposed for the role of copper, ranging from suppression of a key molecule which transports Aβ from the brain to processing/suppression of APP. Cu binding to APP is considered to be in a specific domain in the extra-cellular portion. In many studies, copper is assumed to be Cu(II), binding to appropriate ligand domains. In addition, argument has been made for the enhancement of Ab and hence disease at low and high Cu concentrations and suppression of Ab formation at intermediate concentrations.
There are no known detailed molecular computational studies involving copper and specific ligand domains involving APP and Ab. Such studies at the molecular level would give/deny credence to various hypotheses regarding Cu and Ab/APP and help rectify apparent contradictions regarding the role of copper. Molecular modeling of ligand domains with copper is the focus of this proposal in order to define probable/improbable mechanisms as proposed in the literature. .The aims of our research are two-fold: first to ascertain the structures and variations of APP and Ab – at least 24 species studied by NMR and X-ray crystallographic techniques have been described in the literature – and to determine the ligand geometries amenable to binding of Cu(I) and Cu(II). Secondly, we shall use state-of-the art molecular modeling programs – specifically the Gaussian 09 (G09) with which we plan to carry out ONIOM calculations – and QTAIM suite of programs which we have used extensively in previous computational studies. The QTAIM calculations will confirm the validity of the proposed metal-ligand coordination and characterize the metal-ligand bonding. G09 calculations will be used to confirm these co-ordinations and the associated metal-ligand binding coordination and binding energies. The information on ligand structures will be obtained from critical analysis of the literature of APP etc. We expect that the results will allow the APP/ Ab research community to better focus on energetically viable hypotheses to account for the build up/suppression of Ab in the brain
Last update: march 12, 2010; nhw