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Tyler O'Neal, Staff Editor ACADEMIA June 21, 2022, 12:21 pm

MD simulations of proteins help unravel why chemotherapy resistance occurs

Markus Seeliger and colleagues assess how molecular mutations affect the release of a leading drug for leukemia 

Understanding why and how chemotherapy resistance occurs is a major step toward optimizing treatments for cancer. A team of scientists including Markus Seeliger, Ph.D., of the Stony Brook Cancer Center and Renaissance School of Medicine at Stony Brook University, believe they have found a new process through which drug resistance happens. They are using a supercomputer simulation model that is helping them understand exactly how molecules interact with the cancer drug Imatinib (known as Gleevec) in the chemotherapy-resistant process. Imatinib treats chronic myeloid leukemia (CML) highly effectively, yet many late-stage patients experience drug resistance which renders the drug minimally effective at that stage. Three-dimensional structure of the cancer drug target Abl kinase (grey) bound to the anti-cancer drug imatinib. Normally, the drug exits slowing via the blue arrow. A modification in the kinase (red sphere) causes the drug to exit via a fast route (red arrow). Credit: Aziz M. Rangwala

The research is highlighted in a paper published in Angewandte Chemie and builds upon previous research in 2021.

Imatinib inhibits the BCR-Abl protein kinase, an overly active cellular signaling machinery in CML. In the study, researchers showed that variations in the building plan of the kinase can make it harder for Imatinib to bind to the kinase and also speed up drug release from the kinase. In the Angewandte Chemie paper, the research team took the computational methodology – developed by Pratyush Tiwary from the University of Maryland – that enabled them to study the very slow release of Imatinib from the kinase.

“This method in itself is a major technical achievement that extends computational abilities for drug resistance research, and importantly led to us being able to predict how rapidly healthy and mutant proteins would release this drug,” says Seeliger, Associate Professor in the Department of Pharmacological Sciences. “For the first time, we could see the release of a drug from a protein in such detail and accuracy. Moreover, we could show that the mutation changes fundamentally within the exit route of the drug from the protein.

“This is important since the speed of the drug release may be just as important for the therapeutic effect of a drug as how tightly a drug binds to the protein.”

Seeliger further explains that the method could provide a foundation for understanding the molecular mechanisms behind chemotherapy resistance.

More broadly, the implications of what they discovered are that if scientists can understand how drugs are released from their proteins, they may be able to design drugs with a slower release and higher therapeutic impact. Additionally, if rapid drug release could cause drug resistance, and clinicians can show this is happening, they may be able to re-activate the drug effectiveness by asking the patient to take the drug more frequently.

The groundwork for the mutation testing via the computational method was outlined. Seeliger and colleagues tested how imatinib binds to mutations in patients with imatinib-resistant CML. They found that the majority of mutations readily bind to imatinib, so that posed the question of just how do these mutations cause resistance in patients? The researchers then identified several mutants which bound imatinib readily but they release the drug much faster.

After identifying these mutants with a faster drug release, the team used nuclear magnetic resonance (NMR) and molecular dynamics to link the protein to drug disassociation – underlying the importance of drug disassociation kinetics for drug efficacy. This enabled them to identify a novel mechanism of imatinib resistance.

Japan unveils the mysteries of the genome structure in the human cell nucleus using simulation

Tyler O'Neal, Staff Editor ACADEMIA June 21, 2022, 5:15 am

A team of researchers at Nagoya University in Japan has created a 3-Dimensional computational simulation of the process of genome structure formation in the human cell nucleus. They expect the model to contribute to the understanding of cellular regulatory mechanisms and diseases, such as cancer, that damage the genome.  New modeling technique provides a platform to investigate the relationship between the structure, dynamics, and functions of the human genome  CREDIT Shin Fujishiro, Masaki Sasai

The three-dimensional structure of the genome plays a vital role in regulating the DNA functions of animal and plant cells because it affects its reading and replication. Shin Fujishiro and Masaki Sasai, Professor Emeritus of Nagoya University’s Department of Complex Systems Science, Graduate School of Informatics, constructed a 3D model by analyzing the whole genome of human cells. They used this model as a platform to investigate the relationship between the structure, dynamics, and functions of the human genome. 

“The spatial organization of DNA and its dynamic movement in cells are crucial for understanding cell functions,” Professor Sasai explains. “Researchers have devoted considerable effort to explaining DNA organization in cells by developing various experimental methods, including biochemical and microscope technologies, but now a unified picture is required. Our research introduces the first computational model that can quantitatively analyze various data from the full genome of human cells in a consolidated way.” 

To help understand the process, the researchers investigated chromatin. Chromatin is a mixture of DNA with proteins that exist in cells as a way to keep the DNA compact. According to their model, chromatin is unevenly distributed and during the unfolding process that occurs during cell division, repulsive forces among the chromatin chains induce them to separate. This same force also separates chromatin into active and inactive compartments in the nuclei. The researchers found that their proposed mechanism clarified biochemical and microscopic findings of previous studies.  

Professor Sasai adds: “Our model provides an indispensable tool and an original perspective in cell biology. From the computational model developed in this research, we can determine how perturbations in cells affect genome dynamics and organization. We can also investigate how disease cells, including various cancer cells, affect the genome. It allows us to more deeply analyze the relationship between genome structure and transcription regulation. The model developed in this research provides a fundamental tool and a new viewpoint in cell biology.” 

University of Exeter makes a pivotal breakthrough in the quest to control light to evolve the next generation of quantum sensing, supercomputing

Tyler O'Neal, Staff Editor ACADEMIA June 20, 2022, 12:12 pm

The team of researchers, including Dr. Oleksandr Kyriienko from the University of Exeter, has shown that controlling light can be achieved by inducing and measuring a nonlinear phase shift down to a single polariton level. This is a pivotal breakthrough in the quest to control light to evolve the next generation of quantum sensing and supercomputing.

Polaritons are hybrid particles that combine properties of light and matter. They arise in optical structures at strong light-matter coupling, where photons hybridize with underlying particles in the materials – quantum well excitons (bound electron-hole pairs).

The new research, led by the experimental group of Prof D Krizhanovskii from the University of Sheffield, has observed that interaction between polaritons in micropillars leads to a cross-phase-modulation between modes of different polarization.

The change of phase is significant even in the presence of (on average) a single polariton and can be further increased in structures with stronger confinement of light. This brings an opportunity for quantum polaritonic effects that can be used for quantum sensing and supercomputing.

Theoretical analysis, led by Dr. Oleksandr Kyriienko, shows the observed single polariton phase shift can be further increased, and cascading micropillars offer a path toward polaritonic quantum gates.

Quantum effects with weak light beams can in turn help detect chemicals, and gas leakage, and perform computation at largely increased speed.

Dr. Kyriienko said: “The experimental results reveal that quantum effects at a single polariton level can be measured in a single micropillar. From the theory point of view, it is important to increase phase shifts and develop the system into an optically controlled phase gate. We will see more efforts to build quantum polaritonic lattices as a quantum technology platform.”

Polaritons have proven to be an excellent platform for nonlinear optics, where particles enjoy increased coherence due to cavity field and strong nonlinear from exciton-exciton scattering.

Previously, polaritonic experiments led to the observation of polaritonic Bose-Einstein condensation and various macroscopic nonlinear effects, including the formation of solitons and vortices. However, the observation of quantum polaritonic effects in the low occupation limit remains an uncharted field.

The study shows that polaritons can sustain nonlinearity and coherence in extremely small occupations. This triggers a search for polaritonic systems that can further enhance quantum effects and operate as quantum devices.

Dr.. Paul Walker, the corresponding author of the study, explains: “We have used high-quality micropillars from gallium arsenide provided by collaborators from the University of Paris Saclay, France. These pillars confine modes of different polarization that are close in energy. By pumping light into one of the modes (fundamental), we probe a signal sent into another (higher energy) mode, and observe that the presence of a weak (single photon) pulse leads to polarization rotation. This can be seen as a controlled phase rotation.”

The senior author of the study Prof Krizhanovskii concludes: “In the presented experiment we have made a first step to see single-polariton effects. There is certainly a room for improvement. In fact, using cavities of smaller size and optimizing the structure we expect to increase phase shift orders of magnitude. This will establish the state-of-the-art for future polaritonic chips.”

  1. MIT built model helps identify mutations that drive cancer
  2. Portland State math prof wins $2.1M grant to expand data-driven research, training

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