Tomorrow's Health, Today's Research

Dr. Irina Paci

Associate Professor, Department of Chemistry, University of Victoria
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Phone: 250-472-4946
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Research Areas: theoretical and computational chemistry, disease process simulation
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Research Profile

Computational Chemistry and Disease: How mathematics can help us better understand rheumatoid arthritis

Dr. Irina Paci uses theoretical and computational chemistry in order to better understand, and test out new theories, of human disease.

Theoretical chemistry is a method of predicting how chemical processes will play out based on related phenomena. It is essential to understanding the molecular events involved in chemical processes that are often too difficult, costly, and even dangerous to carry out in live experiments.

Computational chemistry relies on powerful computers in order to implement the complex mathematical formulas that are required to predict and simulate disease processes, right down to the molecular level.

Paci’s research team predominantly relies on the classical method of computational chemistry, which looks at the particle-like characteristics of atoms within a molecule. While quantum chemistry, a far more expensive and time consuming method that relies on the principles of quantum mechanics to quantify the wave-like characteristics of electrons, is used to gather more accurate and detailed information about very specific molecular pockets of interest.

So how exactly does mathematics come into play when trying to understand the molecular underpinnings of disease in the human body?

“Mathematical formulas offer us a way of describing the relationships and interactions that occur between molecules,” says Paci.

Each type of interaction whether it be a Van der Waals force, Coulomb force, or polarization that occurs between two atoms can be described by a discrete equation. These equations can then be combined into a single, albeit complex, formula that essentially sums up the entirety of interactions at play within the molecule of interest.

The mathematical product provides researchers with a whole slew of information about what is occurring at a molecular level, including information about the types of bonds and forces present; the amount of energy consumed or released, reaction rates and ligand-substrate preferences.

More simply put, computational chemistry allows us to more fully understand the steps involved in the binding that occurs between biomolecules. And in Dr. Paci’s particular field of research, the biomolecules of interest are the self-antigen peptides, antigen presenting cells, and MHC2 complexes involved in rheumatoid arthritis (RA).

Paci’s interest in disease modelling began after she was approached by a local rheumatologist who was looking for assistance with some new theories regarding the causal agent behind RA.

Compared to other autoimmune diseases, RA has, on the surface, a relatively simple disease process with concrete diagnostic tests that make it ideal for computational analysis. A predisposition to RA is associated with individuals who possess any one of about 10 unique genetic sequences.

Paci is looking at why these particular genetic sequences leave individuals vulnerable to immune system defects in which normal pieces of host proteins, or ‘self’, are misidentified as foreign invaders, or ‘other’. What chemical processes are involved in the binding events and how exactly does a breakdown in the whole string of immune reactions occur?

Apoptosis, more commonly known as programmed cell death, is a normal process in which old or faulty cells are broken down and recycled. In RA, however, bits of protein debris created from this breakdown cycle or from inflammation specifically, citrullinated-proteins called self-antigens become bound to antigen presenting cells that contain certain sequences of amino acids. This entire complex is then incorrectly labeled as ‘foreign’, causing the body’s immune system to wage an unnecessary attack on itself.

“An antigen presenting cell is waving its hands saying, ‘I’ve got a nasty here!’ But, even if your genetics predispose you to this type of binding event, it doesn’t necessarily mean that you’re going to get RA,” says Paci.

This is because environmental triggers, such as smoking, also play a huge role in precipitating the disease.

Currently, treatment of RA relies on drugs that attack the troublesome products of this cycle from downstream, reducing inflammation, or aiming for a suppression of entire branches of the body’s immune response. This can be ineffective in some individuals, and even when effective, can leave patients vulnerable to all kinds of infections. The common cold can turn into a deadly illness.

One of the questions Paci is asking is what would happen if we interfered with a particular enzyme that results in the type of cell breakdown that produces these citrullinated forms of debris?

By learning more about the interactions that are occurring at a molecular level, Paci is hoping to facilitate an intervention that focuses on upstream processes, isolating the faulty step, and producing a more targeted treatment with fewer side effects.

Paci has no intention of limiting her work to just one disease. In time, she hopes to tackle more complicated diseases, particularly those that share common elements with RA, yet have even more limited treatment options.

“Ultimately, I would really like to get my hands into multiple sclerosis (MS), to get an understanding of how MS works,” says Paci.