Portraits of Rick Page and Dominik Konkolewicz

Miami chemists’ breakthrough technique enables design at the interface of chemistry and biology

A technique developed by Miami University associate professors of chemistry and biochemistry Dominik Konkolewicz and Rick Page may help enable more rapid and efficient development of new materials for use in pharmaceuticals, biofuels, and other applications.

Konkolewicz and Page’s technique uses nuclear magnetic resonance (NMR) technology to illuminate how proteins and synthetic polymers interact in chemical substances known as bioconjugates.

Why bioconjugates are useful

Proteins can be used to catalyze chemical reactions that are useful in many applications. For example, protein enzymes are used to produce high-fructose corn syrup and insulin is used to treat diabetes. But some proteins are active for only a very short time or they break down easily, so it’s just not practical – or cost-effective – to use them. Protein bioconjugates overcome proteins’ limitations by attaching synthetic molecules, often polymers, to the protein.

“Proteins have fantastic performance,” Konkolewicz says, “but there’s not a lot of flexibility in the chemistry we can put into a protein. Polymers offer a huge diversity of structure and function that we can incorporate in to extend the life of the protein or enhance its ability to withstand extreme conditions.”

Already there is some commercial development of bioconjugates, such as antibody-drug conjugates used to treat cancer, although the guidelines for how to improve the performance of these substances remains elusive.

Developing new, useful bioconjugates is often difficult and expensive because the process traditionally relies on trial and error: scientists throw a lot of polymer candidates against a proverbial wall of proteins to see what “sticks” in the form of enhanced performance. But just as it doesn’t make sense to throw a tennis ball at a Sheetrocked wall expecting it to stick, it doesn’t make sense to throw certain polymers at certain proteins expecting them to stick.

Accelerating development through rational design

We understand the nature of tennis balls and drywall well enough to know that “sticking” is not a possible outcome of their interaction, but Page says that scientists don’t always understand the nature of proteins and polymers well enough to make similar predictions when it comes to bioconjugation.

“In many cases, we know the structure of the protein, but we don’t know the structure of the polymer. We don’t know what shape it is, where it attaches to the protein, or how it wraps around or interacts with the protein,” Page says.

What’s needed, Konkolewicz and Page say, is a set of rules that would enable rational design of new bioconjugates. Such rules would allow chemists to look at the structure of a target protein and design a polymer molecule of the right size, shape, and function to fit it specifically.

Schematic showing a synthetic polymer (teal tube) conjugated to a protein (cluster of red, blue, and grey spheres). The purple sleeve on the polymer is a reporting group, the key to Konkolewicz and Page’s technique.

“It would be great to be able to say, ‘Okay, here’s the protein I have. Here are the ways I need to stabilize it, and here are the sorts of polymers we can use for that,’” Page says.

The technique Page and Konkolewicz have developed is the first step in enabling the establishment of such a set of rules.

While previous techniques for examining interactions between proteins and polymers in bioconjugates relied on, for instance, neutron beams – very expensive equipment available at a limited number of facilities around the world – the Miami chemists’ technique uses readily available nuclear magnetic resonance (NMR) technology. The key to the technique is placing reporting groups on the synthetic polymers. These reporting groups act something like beacons, allowing researchers to see how close a polymer is to a protein, when the bioconjugate is in an NMR instrument.

The accessibility of NMR technology is important because it vastly increases the capacity of the research community to make discoveries.

“We can’t look at every relevant protein ourselves,” Konkolewicz says. “We’d have to live for 500 years to do that. By making it accessible, we allow other groups to examine their proteins of interest – catalytic proteins, like our lab focuses on, or therapeutic proteins, or whatever type they study. This technique provides scale.”

A breakthrough made possible by Miami’s unique environment

Fundamentally, Konkolewicz and Page’s technique enables chemists from around the globe to collaborate on the establishment of a set of design rules to guide more rapid development of bioconjugates that are both effective and affordable for use in industrial applications, including pharmaceuticals and biofuels. That’s a fitting outcome for a research effort that was itself born out of collaboration.

It’s been historically uncommon for scientists from different subfields to team up as Konkolewicz, a synthetic chemist, and Page, a biochemist, have. Konkolewicz and Page say their advance owes to the fact that Miami University fosters collaboration and encourages exploration across a broad range of expertise.

“The environment that we have here at Miami, and the ability and encouragement for groups to collaborate with each other here, has really set us up in the right environment to come up with this breakthrough technique,” Page says.

Another aspect of Miami’s unique environment is the deep involvement of undergraduate students in research. Four undergraduate students from Konkolewicz’s and Page’s labs were named as authors of an article reporting on their technique, which was recently published in the open-access flagship Royal Society of Chemistry journal, Chemical Science:

  • Caleb Kozuszek, a biochemistry major who worked in Konkolewicz’s lab prior to his graduation in 2020
  • Ryan Parnell, a biochemistry major who worked in Konkolewicz’s lab prior to his graduation in 2020
  • Jonathan Montgomery, a biochemistry major who worked in Page’s lab prior to his graduation in 2020
  • Nicholas Damon, a biology major who worked in Konkolewicz’s lab prior to his graduation in 2018

In addition to mentoring undergraduate members of their respective teams, PhD students Kevin Burridge (Konkolewicz’s lab) and Ben Shurina (Page’s lab) made other substantial contributions to the work and are named as the publication’s first and second authors, respectively. Jamie VanPelt, a former PhD student of Page’s who graduated in 2018, is also named as an author.

Page and Konkolewicz say Miami’s commitment to facilitating research collaborations is further reflected in the level of support they have received from professional staff in the university’s facilities, including EPR instrumentation specialist Rob McCarrick and NMR/MS specialist Theresa Ramelot, both of whom are named as authors on the Chemical Science article.

Konkolewicz and Page’s research was supported by a grant from the U.S. Army Research Office.

Originally appeared as a “Top Story” on Miami University’s News & Events website.

Photos of Rick Page and Dominik Konkolewicz by Miami University. Schematic provided by the Konkolewicz lab.

Portraits of Dominik Konkolewicz and Rick Page flank an image of coronaviruses.

Two Miami University researchers receive NSF RAPID grant to develop coronavirus-attacking materials

Materials will help limit indirect contact transmission of COVID-19

Two Miami University researchers in protein, polymer and materials chemistry received a Rapid Response Research (RAPID) grant from the National Science Foundation (NSF) for a project that will address the spread of the novel coronavirus.

They received $181,849 to develop materials that can be used to prevent indirect contact transmission of the SARS-CoV-2 coronavirus responsible for COVID-19.

Dominik Konkolewicz and Rick Page, both associate professors of chemistry and biochemistry, are the primary and co-investigators of the project.

Reduce indirect contact transmission of COVID-19

The virus responsible for the COVID-19 pandemic is especially concerning for indirect contact transmission, since it can remain active on various surfaces for extended periods of time, Konkolewicz said.

If a person infected with COVID-19 deposits active viral particles (droplets or aerosols) on frequently touched surfaces, the disease can be transmitted if an uninfected person picks up the active viruses from the contaminated surface.

In this way, the disease can be spread even if the two individuals do not ever come in direct contact with each other. Since the virus can remain active on surfaces for days, there is an increased risk of indirect contact transmission.

To help limit this, Konkolewicz and Page will develop materials that can capture and inactivate the coronavirus on surfaces.

Capture and inactivate the virus

Through their work in synthetic polymer chemistry and protein chemistry, the researchers plan two complementary approaches in developing coronavirus-attacking materials:

Inactivate: One approach is to disrupt the lipid layer/lipid envelope in the coronavirus. This lipid envelope is critical to the structure of the virus and also to its infection mechanism. “If we disrupt the lipids, we can inactivate the coronavirus, such that it cannot infect a new individual,” Konkolewicz said. (Handwashing with soap is one example of disrupting the lipid layer to inactivate the virus).

Capture: The other approach is to capture and trap the coronavirus spike proteins within the synthetic material. This way the virus cannot leave and provide a path for a new infection.

Combined: The researchers will also develop materials with both capture and inactivation capabilities. This two-pronged approach tethers the virus to the surface to allow for increased opportunities to attack and inactivate it, Page said.

The new materials they develop could be adapted or coated onto existing high touch surfaces to limit indirect contact transmission, Konkolewicz said. The polymers will form a tough network to ensure the material performs for an extended period of time.

Konkolewicz and Page will also develop content on the importance of polymer materials in healthcare applications. This will be distributed through YouTube channels for accessibility to the public.

About the researchers

Konkolewicz researches responsive, or “smart” polymer materials and materials that contain both synthetic and biological components. He was awarded an NSF CAREER Award for self-healing polymers in 2018. He was named a 2018 Young Investigator by the American Chemical Society-Polymer, Materials Science, and Engineering section and he received the 2018 Polymer Chemistry Emerging Investigator Award. He and his research team have multiple research collaborations with colleagues in chemistry, biochemistry, chemical engineering and mechanical engineering. He was named a Miami University Junior Faculty Scholar in 2018.

Follow Konkolewicz on Twitter @PolyKonkol.

Page researches the structure, dynamics and mechanisms of action for proteins in a range of biologic and synthetic systems. He was named a Miami University Junior Faculty Scholar in 2016. He received an NSF Career grant in 2016 for his research on protein quality control. In 2018 he received a five-year MIRA (Maximizing Investigator’s Research Award) — one of Miami’s first two — that supports his research projects on protein quality control and antibiotic resistance. He has multiple research collaborations with colleagues in chemistry, biochemistry and bioengineering.

Follow Page on Twitter @ThePageLab.

NSF RAPID grants

The grant for “RAPID: Viral Particle Disrupting and Sequestering Polymer Materials applied to Coronaviruses,” will support the research of Page and Konkolewicz for one year and support three graduate students.

RAPID grants give the NSF a way to help fight the pandemic by supporting scientists doing relevant work across many disciplines, according to the foundation. They may be funded for up to $200,000 and up to one year in duration, with an average award size of $89,000.

In March Congress gave NSF an extra $75 million in the CARES Act stimulus funding to spend on research projects that will help “prevent, prepare for, and respond” to the novel coronavirus.

Written by Susan Meikle, Miami University News and Communications. Originally appeared as a “Top Story” on  Miami University’s News and Events website.

Photos of Dominik Konkolewicz and Rick Page by Miami University Photo Services. Image of coronaviruses by By U.S. Army. Public domain.

Dominik Konkolewicz helps a student in the classroom. Part of a periodic table is visible in the background.

Dominik Konkolewicz receives CAREER Award from the National Science Foundation

Dominik Konkolewicz and a student work with some equipment in Konkolewicz's lab.
Dominik Konkolewicz (right) has been awarded an NSF CAREER grant in support of his polymer research.

Almost everyone has experienced the disappointment that comes along with the first scratch on a new car, a freshly painted wall, or a just-out-of-the-box cell phone. But what if that scratch were just a temporary thing? What if the car or wall or phone could repair itself and no one would ever know the scratch had been there? If Dominik Konkolewicz has anything to do with it, that fantasy may one day become reality.

Konkolewicz, an assistant professor of chemistry and biochemistry at Miami University, recently received a CAREER grant from the Faculty Early Career Development program of the National Science Foundation (NSF).

The NSF CAREER grant is one of the organization’s most prestigious awards in support of junior faculty who “exemplify the role of teacher-scholars through outstanding research, excellent education, and the integration of education and research within the context of the mission of their organizations.”

Konkolewicz is the ninth scientist at Miami to be awarded a CAREER grant. He and his group will receive $600,000 of funding over five years for his research program on polymers. This award brings the number of currently active CAREER grants at Miami to two.

“If you look around a room, and you remove the air, metals, ceramics, and the small amount of water, just about everything else is a polymer,” Konkolewicz says.

Polymers can be natural or synthetic. Natural polymers include cellulose, which is the main component of wood and paper, and proteins or DNA that are essential for life processes. Among the dozens of commodity synthetic polymers are polyethylene milk jugs and plastic wrap; polystyrene packing materials; polyvinylaacetate (PVA) and epoxy glues; and PET soda and water bottles. Polymers are also included as components of paints and other coatings used to finish surfaces like those of cars, walls, and cell phones.

From a chemistry perspective, polymers consist of smaller molecules, or repeating units, linked together to form a larger molecule. This larger molecule, or macromolecule, is like a necklace, with dozens to tens-of-thousands of smaller molecules making up the individual links. In many useful materials, such as cured epoxy glue, soft contact lenses, and the rubber used in tires, long polymer chains are linked to form a mesh or network-like structure at the molecular level.

“The links that bind these chains together are a little like staples,” Konkolewicz says. “They’re permanent. When a material becomes damaged or fractured, the material becomes useless because there’s no way to recover the original properties.”

Konkolewicz’s work focuses on creating links between the chains that he says are more like paper clips than like staples, ones that can be reused many times. If one link is damaged, it can be exchanged for another one, allowing the material – whether it’s wall paint or a truck tire – to heal itself when scratched or punctured.

Konkolewicz says the tradeoff in this kind of chemistry, since it was pioneered in the late 1990s and early 2000s, has been between dynamism and stability. The types of “paper clips” used to hook units together would either allow a material to recover its original properties very quickly, or allow it to maintain its original shape over time, but typically not both.

To understand this tradeoff, we can think about truck tires. If they were made out of a material that could heal quickly when punctured by a nail picked up on the road, drivers could avoid the time, expense, and hassle of being stuck with a flat. However, if that same highly dynamic material were also highly unstable, the tires would lose their shape as they were squeezed between the truck and the road. That’s exactly the dilemma Konkolewicz says currently exists in this type of materials science.

His innovation is to introduce two different types of links in the same material. One type of link would allow the material to heal itself quickly, while the other – which would be activated by applying heat, pH, or light – would “lock in” the permanent shape. In the case of truck tires, that means they could both recover from a nail puncture and remain perfectly round.

Another consideration Konkolewicz says is important in materials science is toughness, or the ability to withstand seemingly minor damage. Once a brittle material acquires a small chip or other defect, any little bump could cause it to shatter. Konkolewicz says the types of dynamic bonds that he is using can increase material toughness, extending the useful lifetime of products made from those materials.

Konkolewicz’s work has clear implications for sustainability. “If you don’t need to throw something out over time, if something has a longer lifetime, that’s a huge benefit,” he says. “It’s a much smaller drain on resources.”

Konkolewicz currently supervises eight graduate students and has 11 undergraduates on his team. He has also mentored an additional graduate student who has since graduated. These students work with Konkolewicz on his CAREER project, as well as on his other projects involving conjugation of synthetic materials to enzymatic proteins and development of light driven chemical and polymerization processes.

All NSF CAREER projects include an integrated education objective. Konkolewicz will conduct community-based STEM outreach for K-12 students in collaboration with Dayton Public Schools and the Public Library of Cincinnati and Hamilton County. In addition, he will continue developing innovative activities to use in the undergraduate classroom. For example, he plans to expand a pilot project in which students use YouTube as a forum to reflect on how they overcame challenges in their studies and to share these strategies with their peers. The CAREER grant will also provide funds for a student from underrepresented groups to work in Konkolewicz’s lab each summer.

Konkolewicz received his doctorate from the University of Sydney in 2011 and was a visiting assistant professor/senior research chemist at Carnegie Mellon University from 2011 to 2014.

Written by Heather Beattey Johnston, Associate Director of Research Communications, Office for the Advancement of Research and Scholarship, Miami University.

Photos by Jeff Sabo, Miami University Photo Services.