Public Abstract

DE-SC0025338: Ab Initio Modeling Capabilities for Simulating DNA Damage Under Ionizing Radiation

Award Status: Active

Institution: University of North Carolina at Chapel Hill, Chapel Hill, NC
UEI: D3LHU66KBLD5
DUNS: 608195277

Most Recent Award Date: 08/19/2024
Number of Support Periods: 1
PM: Kulkarni, Resham

Current Budget Period: 09/01/2024 - 08/31/2025
Current Project Period: 09/01/2024 - 08/31/2027
PI: Kanai, Yosuke

Supplement Budget Period: N/A

Public Abstract

Ab Initio Modeling Capabilities for Simulating DNA Damage Under Ionizing Radiation Yosuke Kanai, University of North Carolina at Chapel Hill (Principal Investigator) The proposed work will advance the first-principles computational methods and (1) examine how different ionizing radiations induce varying electronic excitation responses and (2) to model how the induced electronic excitations lead to specific DNA damages that impede cellular functions. Over the last few decades, it has become clear that linear energy transfer (or electronic stopping power) itself is not enough to explain experimentally observed differences with the ionizing radiation types. Charged-particle radiation like those of protons and alpha-particles induces cellular responses that are distinctively different from those of photon-based radiations like X/gamma-rays or even those of beta-particles (i.e. electrons). At the fundamental level, the difference arises from the interaction of electrons in DNA/water with the ionizing radiation, and understanding such a quantum-mechanical process is a great challenge. Ionizing radiation leads to the generation of highly energetic holes (and some electron-hole pairs) in DNA and in water, and experimentally observed macroscopic differences on the cellular scale for different types of ionizing radiation are believed to derive from differing electronic responses induced by the radiation. While such a hypothesis is physically sound, the important scientific question is how and why the electronic responses are different depending on the ionizing radiation type, and we need to characterize how the electronic excitation differences lead to different outcomes in terms of molecular-level DNA damage. While answering these fundamental scientific questions has remained a daunting task in the field, without overcoming this challenge as a community, we will not transcend the current crude understanding of the experimental observations. With advanced atomistic modeling based on first-principles theory using high-performance computers, Kanai and his team aim to drastically change how this problem is tackled. Instead of using different empirical models with parameters for different types of ionizing radiation, Kanai will approach the problem by spearheading the development of a unifying first-principles computational method that treats these different types of ionizing radiation on an equal footing. In this first-principles approach, the modeling does not rely on experiments but stands as an equal partner with which experimental observations are scrutinized. Due to the quantum dynamical nature of the interaction between DNA/water and radiation, developing a microscopic understanding of this process has remained elusive. Over the last decade, computational methods for simulating quantum dynamics from first-principles theory have greatly advanced. Kanai’s research program has indeed played an important role in this endeavor, and his work with proton and alpha-particle radiation has been widely disseminated in the field. Additionally, it is necessary to model atomic nuclear responses to the transient state of nonequilibrium electrons in order to understand how atomistic damage of DNA is induced. In this regard, modeling the quantum dynamical nature of atomic nuclei remains a difficult scientific challenge. Kanai and his team will expand on their new computational method development for simulating coupled quantum dynamics of electrons and nuclei in complex heterogeneous environments. Together with the new generation of exascale computers, it is now possible to develop software and perform first-principles modeling of nonequilibrium processes to study DNA damage induced by ionizing radiation without relying on inconvenient empirical parameters.

Ab Initio Modeling Capabilities for Simulating DNA Damage Under Ionizing Radiation

Yosuke Kanai, University of North Carolina at Chapel Hill (Principal Investigator)

The proposed work will advance the first-principles computational methods and (1) examine how different ionizing radiations induce varying electronic excitation responses and (2) to model how the induced electronic excitations lead to specific DNA damages that impede cellular functions. Over the last few decades, it has become clear that linear energy transfer (or electronic stopping power) itself is not enough to explain experimentally observed differences with the ionizing radiation types. Charged-particle radiation like those of protons and alpha-particles induces cellular responses that are distinctively different from those of photon-based radiations like X/gamma-rays or even those of beta-particles (i.e. electrons). At the fundamental level, the difference arises from the interaction of electrons in DNA/water with the ionizing radiation, and understanding such a quantum-mechanical process is a great challenge. Ionizing radiation leads to the generation of highly energetic holes (and some electron-hole pairs) in DNA and in water, and experimentally observed macroscopic differences on the cellular scale for different types of ionizing radiation are believed to derive from differing electronic responses induced by the radiation. While such a hypothesis is physically sound, the important scientific question is how and why the electronic responses are different depending on the ionizing radiation type, and we need to characterize how the electronic excitation differences lead to different outcomes in terms of molecular-level DNA damage. While answering these fundamental scientific questions has remained a daunting task in the field, without overcoming this challenge as a community, we will not transcend the current crude understanding of the experimental observations. With advanced atomistic modeling based on first-principles theory using high-performance computers, Kanai and his team aim to drastically change how this problem is tackled. Instead of using different empirical models with parameters for different types of ionizing radiation, Kanai will approach the problem by spearheading the development of a unifying first-principles computational method that treats these different types of ionizing radiation on an equal footing. In this first-principles approach, the modeling does not rely on experiments but stands as an equal partner with which experimental observations are scrutinized.

Due to the quantum dynamical nature of the interaction between DNA/water and radiation, developing a microscopic understanding of this process has remained elusive. Over the last decade, computational methods for simulating quantum dynamics from first-principles theory have greatly advanced. Kanai’s research program has indeed played an important role in this endeavor, and his work with proton and alpha-particle radiation has been widely disseminated in the field. Additionally, it is necessary to model atomic nuclear responses to the transient state of nonequilibrium electrons in order to understand how atomistic damage of DNA is induced. In this regard, modeling the quantum dynamical nature of atomic nuclei remains a difficult scientific challenge. Kanai and his team will expand on their new computational method development for simulating coupled quantum dynamics of electrons and nuclei in complex heterogeneous environments. Together with the new generation of exascale computers, it is now possible to develop software and perform first-principles modeling of nonequilibrium processes to study DNA damage induced by ionizing radiation without relying on inconvenient empirical parameters.