“We live in a world of heterogeneity,” said Kolomeisky, who is a chemistry professor and department chair. “In chemistry, heterogeneity is considered a nuisance and it’s frequently thrown away or averaged out. The idea behind this project is to use heterogeneity as a tool to better understand the molecular mechanisms at the basis of certain chemical and biological processes.”
One such process is catalysis, which involves speeding up the rate of a chemical reaction by means of catalysts, compounds that do not get consumed by the reaction. Our bodies rely on catalysts known as enzymes to perform essential functions such as digestion, breathing, building muscle, transmitting nerve signals and clearing out toxins. Major industries rely on catalysis to generate or optimize their products ¾ be it drugs, fuels, food, cosmetics, etc.
The molecular structure of a catalyst molecule includes an area with a unique shape that facilitates a given chemical reaction. This area is known as an “active site.” In theory, it is assumed that the individual molecules of a given catalyst compound are identical. In practice, however, this is not the case.
“Active sites are not identical even though experimentalists assume that they are,” Kolomeisky said. “I'm trying to develop theories that calculate the dynamics of a chemical reaction while taking into account the heterogeneity of active sites, and would like to establish measurable, quantitative parameters to assess the degree of heterogeneity for a given reaction.
“I think studying the dynamics of catalyzed reactions could help us understand the underlying molecular mechanisms involved.”
Kolomeisky also plans to explore how heterogeneity impacts the efficacy of antimicrobial peptides, molecules that help organisms defend themselves against encroaching bacteria, fungi, viruses and even cancer.
“All organisms produce these peptides,” Kolomeisky said. “They are relatively short molecules ⎯ between 10 and 50 amino acids ⎯ that are efficient antibacterial agents.”
Antimicrobial peptides are a possible solution to growing bacterial resistance to antibiotics, making them a prime target for research. The recent pandemic has also spurred interest.
“The big advantage of antimicrobial peptides in comparison to antibiotics is that developing resistance to them is much less likely,” Kolomeisky said. “This might be the future of medicine.”
Combinations of two or more peptides are not only likely to be more effective at combating infection, but they could also generate lower toxicity compared to a higher dose of a single peptide.
“If you take two different kinds of antimicrobial peptide, then you’ll likely need a lower concentration for each of them, which improves the odds that toxicity will be lower,” Kolomeisky said. “It’s also less likely that bacteria will be able to develop resistance to a combination of peptides rather than to a single one.
“We’ll develop theoretical physio-chemical models in support of the idea that this increased efficiency of a combination of antimicrobial peptides is due to cooperative binding to the microbial membrane.”
Using machine learning, Kolomeisky will comb through the library of over 1,000 known antimicrobial peptides and earmark the most promising combinations for further research and future antibacterial drug development.
“The question is not only which two peptides to combine, but also in what concentrations,” Kolomeisky said. “Two is better than one, but we have an idea that three would be even better than two. So, the question is, how do we quantify this, what is the reason for it?”
Early-stage cancer development is another biological process where quantifying heterogeneity could shed light on the underlying molecular mechanisms involved, possibly enabling the development of new therapeutic targets.
“We’d like to understand the role of heterogeneity in the cancer initiation process, from a chemical point of view,” Kolomeisky said. “In chemistry, looking at change in the concentration of a compound over time tells you something about the underlying mechanism of the reaction that’s taking place.
“I want to focus on the processes that lead to the formation of a tumor and investigate the following problem: In normal tissue, cells of the same type are not identical, even though they might look similar. This heterogeneity means they will have slightly different properties that will affect how the cancer evolves.
“I hope that looking at the temporal evolution of cancer initiation or progression will teach us something about what’s happening at the cellular level in these early stages. We're trying to develop network models, where we’re assuming that each cell is a node within a network, and changes in the system correspond to changes along the network. Using this network model, we can better take into account the role of cellular heterogeneity in cancer progression.”
The fourth project area concerns lysis, or the breakdown of bacterial cell membrane due, in this case, to viruses known as bacteriophages.
“Bacteriophages stimulate bacteria to produce a specific protein ⎯ in this context, we'd like to use holin ⎯ in excess amounts,” Kolomeisky said. “The holin accumulates at the cell membrane, and above a certain threshold value the membrane breaks.”
Lysis exhibits unusually low heterogeneity in reaction time distribution, contradicting the expected reaction rate.
“We'd like to understand the mechanisms and dynamics of these processes, because experimental measurements found that membrane rupture occurs within a very narrow time distribution,” Kolomeisky said. “From the time zero when the bacteriophage enters the cell to the time right before the bacterial cell breaks, the distribution of reaction times is much narrower than you would expect.”
In addition to research, the project involves a teaching component.
“The project will provide opportunities for students and postdoctoral researchers to do multidisciplinary training because the work involves chemistry, physics, biology, computer science and applied mathematics,” he said. “We also plan to host visiting high school students and foster participation for underrepresented groups in STEM education.”
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CAPTION: Anatoly Kolomeisky is a chemistry professor and department chair at Rice. (Photo by Gustavo Raskosky/Rice University)
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