Research Interests; 2010
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
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Last update: march
12, 2010; nhw