Computational Chemistry Computational Biology and at the University of Kentucky R. Michael Sheetz,...

Computational Chemistry

Computational Biologyand

at the

University of Kentucky

R. Michael Sheetz, PhD

Center for Computational Sciences

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The University of Kentucky occupies a unique position

chemistry within the National Computational Science

within the computational chemistry community.

Our university is the designated site for computational

and industry researchers working together to develop

Alliance (Alliance) - a group of university, government,

an advanced, national computational infrastructure for

scientific computing.

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As a national site for computational chemistry, we have

atmospheric & environmental chemistry

the opportunity to provide computing resources for

involving computational chemistry including

research covering a very diverse set of areas and topics

physical organic chemistry

biological chemistry

materials science



Atmospheric and Environmental

Chemistry



Atmospheric Degradation of Isoprene



Although our level of understanding of the biogeochemistry

Atmospheric and Environmental Chemistry

cycles of greenhouse gases, oxidants, and aerosols has increased

substantially during the past 5 - 10 years, our understanding

of the these cycles is far from complete.

One very important greenhouse gas is tropospheric ozone.

The behavior of this gas is extremely complex and is highly

correlated with the efficiency of atmospheric oxidation ( [OH] ).



Consequently, a much better understanding of the pathways


for synthesis and degradation of ground-level ozone is a topic

of considerable interest in atmospheric/environmental chemistry.

Sources of tropospheric ozone include:

stratospheric ozone

in situ photochemistry in the atmosphere

emission of volatile carbon by natural resources



The single most important volatile carbon contributing to ground-level ozone synthesis is isoprene (2-methyl-1,3-butadiene)


In daylight, reaction with OH is the primary initiator of isoprene degradation in the atmosphere.



In the presence of NOx , atmospheric decomposition of isoprene produces a wide variety of degradation products


isoprene formaldehyde OH, NOx

methyl vinyl ketone

methacrolein

3-methylfuran

organic nitrates

a large variety of carbonyl compounds



The variety of carbonyl products formed in the decomposition of isoprene has hampered the identification of these products and their yields and has made the elucidation of the pathways for degradation of isoprene in the atmosphere extremely difficult.


One of the current computational chemistry projects being carried out at our facility is an investigation of the atmospheric degradation pathways of isoprene.



Following reaction of isoprene with OH, six alkoxy radicals are initially formed. In this current study, the


of all six alkoxy radicals as well as for the transition states and products for all C – C bond fission pathways that can conceivably occur in the atmosphere is being determined using density function theory (DFT) .

converged structures,

vibrational frequencies, and

energies



Atmospheric Oxidation of NOx




The chemistry of nitric oxide (NO) is of considerable significance as a reactive atmospheric NOx species. The direct oxidation of NO

by O2 to give nitrogen dioxide (NO2)

is thought to play a critical role in processes such as combustion, and can contribute to atmospheric chemistry under conditions of high NO concentration, such as in emissions from power plants or automobiles.

2NO + O2 2NO2

An unusual peroxide, ONOONO, has been proposed as an intermediate in this oxidation reaction.



One of the projects carried out at our facility was an investigation of the O O bond breaking reactions of this unusual peroxide using CBS-QB3 and B3LYP/6-311G* hybrid density functional theory.


The results of this investigation showed that the cis-oriented NO2 correlates electronically with the 2A1 ground state whereas the trans-oriented NO2 correlates electronically with the 2B2 excited state providing an unusual example of conformation-dependent electronic state selectivity.


Computational Biochemistry



Catalytic Mechanism of

Superoxide Dismutases



The superoxide dismutases (SODs) of E. coli and nitroreductase (NR) from E. cloacae serve as two mutually complementary systems in which to study

fundamental aspects of enzymatic redox catalysis

biochemical defenses against oxidative damage

mechanisms of waste detoxification



Redox enzymes combine the reactivity and versatility of transition metal ions and conjugated cofactors with the specificity and selectivity of enzymes.

These enzymes catalyze chemical reactions as energetically demanding as the reductive cleavage of N2 (the second strongest bond known), yet this reduction occurs under relatively mild conditions within the interior of a protein.



A primary area of interest in physical biochemistry is how proteins activate bound cofactors for specific reactions, control them so that other reactions are minimized, and manage to evade irreversible reaction with the cofactor themselves.

One of the current projects in computational biochemistry being conducted at our facility is an investigation of the mechanisms by which proteins determine the redox potential and reactivity of bound flavins.



Catalytic Mechanism of ODCase



The formation of uracil ribose 5’-monophosphate is the final step in the de novo synthesis of pyrimidine nucleotides. The reaction involves the decarboxylation of orotidine 5’-monophosphate and is catalyzed by the enzyme orotidine 5’-monophosphate decarboxylase (ODCase). This reaction requires neither a cofactor or a metal ion for activity.

O

N

NH

O- O2C

ribose-P

O

NH

NO

ribose-P

ODCase

H+ CO2



A proposed mechanism for ODCase catalysis involves proton transfer to either the 2-oxygen (O2) or the 4-oxygen (O4) to promote decarboxylation of the orotate moiety.

One of the projects in computational biochemistry conducted at our facility investigated this proposed mechanism for the decarboxylation of orotate.



The computational chemistry calculations from this investigation suggests that

O4-protonation of orotate followed by decarboxylationis preferred energetically over O2-protonation

the mechanistic basis for the more favorable energeticsof O4-protonation is a greater basicity of the 4-oxygen over the 2-oxygen in the transition state of orotate



Conformation of Proline-Rich

Polypeptides



Proline-rich regions of peptides are believed to adopt an extremely flexible left-handed polyproline II (PPII) helical conformation in solution. However, it is not clear from experimental studies that this is actually true.

One of the projects in computational biochemistry currently being conducted at our facility is an investigation of the conformations adopted by proline-rich peptides and the determinants of a PPII helical conformation in solution. These studies are being carried out using a combination of molecular dynamics and Monte Carlo simulation.



Repair of Damaged DNA



DNA damage is responsible for a number of diseases including various forms of cancer.

Another project in computational biochemistry currently being conducted at our facility is an investigation of the differences in dynamics and conformations of damaged and undamaged DNA and their interactions with DNA repair proteins. The studies that are being carried employ molecular dynamics simulation with the incorporation of dynamic information from NMR spectroscopy.


Materials Science

Computational Chemistry and Materials Science


Certain 2-dimensional C60 structures have been found to exhibit spontaneous magnetization that continues to exist far above room temperature.

Two mechanisms have been proposed to explain how this magnetization originates in these non-metallic materials :

unpaired electrons donated by edge carbon atoms

vacancies within the polymeric carbon

Magnetism in Non-Metallic Molecular Materials (A combination of computational chemistry and condensed matter physics)

Computational Chemistry and Materials Science


Magnetism in Non-Metallic Molecular Materials

Both mechanisms entail the transformation of sp2 to sp3 orbitals in combination with some type of structural rearrangement of the polymer.

One of the current projects in computational chemistry being conducted at our facility involves an investigation of the interplay between structural defects and sp3 hybridization in explaining the origin of the observed spontaneous magnetization in these carbon polymers.


Computational Biology



The characterization of DNA and protein sequences is a problem of continually increasing importance in biology, biochemistry, medicine, and pharmacology. The most commonly used procedure employed in such investigations involves the rapid screening of large databases of DNA and protein sequences.

The most widely used tool for screening of these databases is BLAST (Basic Local Alignment Search Tool). Most commonly, these applications are run as serial searches on a single computer processor.



Unfortunately, the continual input of sequence information into these databases has resulted in an exponential growth in the sizes of these databases. The result has been that single processor searches are becoming extremely inefficient for many sequence investigations.

Recently, a parallel implementation of BLAST has been developed that dramatically accelerates the search of large sequences databases. This application, called TurboBLAST, is currently installed on our supercomputer and is scheduled to begin testing by local users in the very near future.


email address:

[email protected]

Computational Chemistry Computational Biology and at the University of Kentucky R. Michael Sheetz,...

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