Electron transport, the energy-generating process inside living cells that enables photosynthesis and respiration, is enhanced in peptides with a collapsed, folded structure. Interdisciplinary researchers at the Beckman Institute for Advanced Science and Technology combined single-molecule experiments, molecular dynamics simulations and quantum mechanics to validate their findings.

“This discovery provides a new understanding of how electrons flow through peptides with more complex structures while offering new avenues to design and develop more efficient molecular electronic devices,” said lead investigator Charles Schroeder, the James Economy Professor in Materials Science and Engineering at the University of Illinois Urbana-Champaign.

Proteins reside in all living cells and are integral to cellular activities like photosynthesis, respiration (taking in oxygen and expelling carbon dioxide) and muscle contraction.

Chemically, proteins are long sequences of amino acids strung like holiday lights, the different colors representing different amino acids like tryptophan and glutamine.

In a protein’s simplest form (its primary structure) the amino acid string lies flat. But amino acids are prone to mingling; when they interact with one another, the string tangles, causing the structural collapse referred to as protein folding (or secondary structure).

The researchers asked if and how a protein’s structure impacts its ability to conduct electricity — a question not clearly answered by existing literature.

Rajarshi “Reeju” Samajdar, a graduate student in the Schroeder Group, was patiently probing this protein problem by experimenting on one molecule at a time. But Samajdar was not looking at proteins at all. Instead, he focused on peptides, fragments of proteins with a fraction of the amino acids. For this study, Samajdar used peptides with about four or five amino acids, which permitted more granular observation, he said.

Samajdar saw something surprising: stretched-out peptides with a primary structure seemed to be less effective energy conductors than their folded counterparts with a secondary structure. The stark difference between the peptides’ behavior in each state piqued his curiosity.

“Peptides are very flexible. We were interested in understanding how the conductance properties changed as you stretch them out and the peptides transition from a folded secondary structure to an extended conformation. Interestingly, I saw a distinct jump between those two structures, with different electronic properties in each,” Samajdar said.

To verify his observations, Samajdar called on Moeen Meigooni, a graduate research assistant working with Emad Tajkhorshid, a Beckman researcher, professor and the J. Woodland Hastings Endowed Chair in Biochemistry.

The team simulated the peptides’ conformational behavior with computer modelling, confirming the jerky structural shifts Samajdar observed. Leaving no scientific stones unturned, the researchers worked with Martin Mosquera, an assistant professor of chemistry at Montana State University, and Nicholas Jackson, a Beckman researcher and an assistant professor of chemistry at Illinois, to use quantum mechanical calculations to confirm that these two discrete structures were indeed linked to the changes in conductivity.

“We believe that our approach combining single-molecule experiments, structural modelling with molecular dynamics and quantum mechanics is a very powerful approach for understanding molecular electronics,” Samajdar said. “We could have gone straight to quantum, but we didn’t. The computer simulation piece allowed us to study the entire conformational space of the peptides.”

The researchers’ triple-checked results indicate that peptides with a folded secondary structure do conduct electricity better than peptides with an unfolded primary structure. The specific secondary structure they observed formed a shape called the 3₁₀ helix.

Because this work was conducted on peptides, the results lend themselves to a greater understanding of electron transport in larger, more complex proteins and other biomolecules, pointing toward applications in molecular electronic devices like semiconductors that work by switching between two distinct structures.

For the first time, researchers at Tulane National Primate Research Center found that a cancer drug significantly reduced levels of SIV, the nonhuman primate equivalent of HIV, in the brain by targeting and depleting certain immune cells that harbor the virus.

Published in the journal Brain, this discovery marks a significant step toward eliminating HIV from hard-to-reach reservoirs where the virus evades otherwise effective treatment.

“This research is an important step in tackling brain-related issues caused by HIV, which still affect people even when they are on effective HIV medication,” said lead study author Woong-Ki Kim, PhD, associate director for research at Tulane National Primate Research Center. “By specifically targeting the infected cells in the brain, we may be able to clear the virus from these hidden areas, which has been a major challenge in HIV treatment.”

Antiretroviral therapy (ART) is an essential component of successful HIV treatment, maintaining the virus at undetectable levels in the blood and transforming HIV from a terminal illness into a manageable condition. However, ART does not completely eradicate HIV, necessitating lifelong treatment. The virus persists in “viral reservoirs” in the brain, liver, and lymph nodes, where it remains out of reach of ART.

The brain has been a particularly challenging area for treatment due to the blood-brain barrier — a protective membrane that shields it from harmful substances but also blocks treatments, allowing the virus to persist. In addition, cells in the brain known as macrophages are extremely long-lived, making them difficult to eradicate once they become infected.

Infection of macrophages is thought to contribute to neurocognitive dysfunction, experienced by nearly half of those living with HIV. Eradicating the virus from the brain is critical for comprehensive HIV treatment and could significantly improve the quality of life for those with HIV-related neurocognitive problems.

Researchers focused on macrophages, a type of white blood cell that harbors HIV in the brain. By using a small molecule inhibitor to block a receptor that increases in HIV-infected macrophages, the team successfully reduced the viral load in the brain. This approach essentially cleared the virus from brain tissue, providing a potential new treatment avenue for HIV.

The small molecule inhibitor used, BLZ945, has previously been studied for therapeutic use in amyotrophic lateral sclerosis (ALS) and brain cancer, but never before in the context of clearing HIV from the brain.

The study, which took place at the Tulane National Primate Research Center, utilized three groups to model human HIV infection and treatment: an untreated control group, and two groups treated with either a low or high dose of the small molecule inhibitor for 30 days. The high-dose treatment lead to a notable reduction in cells expressing HIV receptor sites, as well as a 95-99% decrease in viral DNA loads in the brain .

In addition to reducing viral loads, the treatment did not significantly impact microglia, the brain’s resident immune cells, which are essential for maintaining a healthy neuroimmune environment. It also did not show signs of liver toxicity at the doses tested.

The next step for the research team is to test this therapy in conjunction with ART to assess its efficacy in a combined treatment approach. This could pave the way for more comprehensive strategies to eradicate HIV from the body entirely.

This research was funded by the National Institutes of Health, including grants from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke, and was supported with resources from the Tulane National Primate Research Center base grant of the National Institutes of Health, P51 OD011104.

“We envision the construction of a quantum interconnect network using the kink states as the backbone,” said team leader Jun Zhu, professor of physics at Penn State. Zhu is also affiliated with Penn State’s Center for 2-Dimensional Layered Materials. “Such a network may be used to carry quantum information on-chip over a long distance, for which a classical copper wire won’t work because it has resistance and therefore cannot maintain quantum coherence.”

The work, published recently in Science, potentially provides a foundation for researchers to continue investigating kink states and their application in electron quantum optics devices and quantum computers.

“This switch operates differently from a conventional switch, where the electrical current is regulated through a gate, similarly to traffic through a toll plaza,” Zhu said. “Here, we are removing and rebuilding the road itself.”

Kink states exist in a quantum device built with a material known as Bernal bilayer graphene. This comprises two layers of atomically thin carbon stacked together, in such a way that the atoms in one layer are misaligned to the atoms in the other. This arrangement, together with the use of an electric field, creates unusual electronic properties — including the quantum valley Hall effect.

This effect refers to the phenomenon of electrons occupying different “valley” states — identified based on their energy in relation to their momentum — also move in opposing forward and backward directions. Kink states are manifestations of the quantum valley Hall effect.

“The amazing thing about our devices is that we can make electrons moving in opposite directions not collide with one another — which is called backscattering — even though they share the same pathways,” said first author Ke Huang, a graduate student pursing a doctorate in physics at Penn State under Zhu’s mentorship. “This corresponds to the observation of a ‘quantized’ resistance value, which is key to the potential application of the kink states as quantum wires to transmit quantum information.”

While the Zhu lab has published on the kink states before, they only achieved the quantization of the quantum valley Hall effect in the current work after improving the electronic cleanness of the devices, meaning they removed sources that could allow electrons moving in opposite directions to collide. They did this by incorporating a clean graphite/hexagonal boron nitride stack as a global gate — or a mechanism that can allow the flow of electrons — into the devices.

Both graphite and hexagonal boron nitride are compounds commonly used as lubricant for paints, cosmetics and more. Graphite conducts electricity well while hexagonal boron nitride is an insulator. The researchers used this combination to contain electrons to the kink states and control their flow.

“The incorporation of a graphite/hexagonal boron nitride stack as a global gate is critically important to the elimination of electron backscattering,” Huang said, noting that this material use was the key technical advancement of the current study.

The researchers also found that the quantization of the kink states remains even when the temperature is raised to several tens of Kelvin, the scientific unit of temperature. Zero Kelvin corresponds to -460 degrees Fahrenheit.

“Quantum effects are often fragile and only survive at cryogenic temperatures of a few Kelvin,” Zhu said. “The higher temperature we can make this work, the more likely it can be used in applications.”

The researchers experimentally tested the switch they built and found that it could quickly and repeatedly control the current flow. This adds to the arsenal of kink state-based quantum electronics widgets that help control and direct electrons — valve, waveguide, beam splitter — previously built by the Zhu lab.

“We have developed a quantum highway system that could carry electrons without collision, be programmed to direct current flow and is potentially scalable — all of which lays a strong foundation for future studies exploring the fundamental science and application potentials of this system,” Zhu said. “Of course, to realize a quantum interconnect system, we still have a long way to go.”

Zhu noted that her lab’s next goal is demonstrate how electrons behave like coherent waves when traveling on the kink state highways.

Other authors include Hailong Fu, a former postdoctoral scholar and Eberly Fellow in physics at Penn State, and a current assistant professor at Zhejiang University, China; and Kenji Watanabe and Takashi Taniguchi, both with the National Institute for Materials Science in Japan.

The U.S. National Science Foundation, the U.S. Department of Energy, the Penn State Eberly Research Fellowship, the Kaufman New Initiative of the Pittsburgh Foundation, the Japan Society for the Promotion of Science and the World Premier International Research Initiative of Japan’s Ministry of Education, Culture, Sports, Science and Technology funded this research.