The investigation and characterization of oxidized biomolecules using quantum models

Mandy Cay Green, Purdue University

Abstract

Oxidative stress causes chemical reactions in which highly reactive species oxidize biomolecules. While oxidative stress is a contributor to cancer, protein aggregation diseases, and aging, chemical mechanisms underlying these biological processes are not well understood. This is because radical oxygen derivatives produced by oxidative stress are short-lived and difficult to spectroscopically measure. This work examines spectral signatures, thermodynamics, and kinetics of oxidation chemistry in protein and lipid systems, using computational quantum methods. This thesis work outlines novel approaches for studying physical chemistry of oxidation reactions and applications of quantum methods to biological systems. Computational methods can utilize either classical or quantum theories, with a choice being dictated by system size. A large size of biological molecules calls for classical methods. On the other hand, radical species, in which electronic degrees of freedom are of importance, are typically examined with quantum methods. However, computational cost and scaling of quantum methods rapidly increases with system size, such that accurate correlated calculations become cost-prohibitive for systems with more than 20-30 atoms. This work explores the challenges of calculating bio-radicals with quantum methods. Early work utilizes traditional ab initio methods and is limited to systems of up to 44 atoms. Later work utilizes the fragment molecular orbital (FMO) method in systems containing 42, 134, and 1000+ atoms. Alanine tripeptide is selected as a model system because it is the smallest peptide to form a protein fold. Reaction dynamics and spectral properties of the oxidized β-structured peptides are reported. A new energy decomposition analysis is applied to hydrogen abstraction in the β-turn, and is used to explore the intramolecular interactions in both neutral and Cα * peptides. FMO computes large molecular systems by dividing them into fragments and performing quantum-mechanical calculations on fragments and their dimers in the Coulomb field of the whole system. The FMO method is applied to lipids and used to investigate the thermodynamics of hydrogen abstraction in several lipid models.

Degree

Ph.D.

Advisors

Slipchenko, Purdue University.

Subject Area

Biochemistry|Physical chemistry

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