The progress in recent years of computing power and development of hybrid simulation methods such as quantum mechanics or molecular mechanics techniques have enabled researchers to investigate very large, highly complex, biological systems such as proteins, which were hitherto inaccessible due to their size, structure, and dynamic complexity.
For the past 12 months, Dominik Marx, Chair of Theoretical Chemistry at the Ruhr-University Bochum, Germany, together with his research team led by Ian Grant, a research associate, have sought to understand the complex nature and role of quantum tunneling phenomena in the catalytic cycles of enzymatic processes. By doing so, the group hopes to show if there are special cases where this non-classical promotion effect increases the catalytic power of enzymes.
The research work of Marx's team is focused on a broad understanding of the structure, dynamics, and chemical reactions of complex molecular systems. Utilizing advanced ab initio (from first principles) simulation methods, and algorithms, in conjunction with capability computing, the team sought to understand these processes via computational means. They wanted to capture and understand complex bio-chemical processes by examining them at the nanoscopic level, i.e. in terms of the motion of individual atoms consisting of nuclei and electrons.
"In some ways, then, it was a natural progression for us to accept the challenge of investigating these esoteric quantum tunneling effects in such overly complex biomolecular systems as enzymes, thus bridging the gap between physics, chemistry, and biology," said Marx.
"This was only possible after significant method development and implementation into the so-called CPMD code [a parallel software designed for first principle based molecular dynamics] in order to marry quantum mechanics or molecular mechanics methodology, with the ab initio path integral technique. This was done by researchers Gerald Mathias and Sergei Ivanov."
Investigating the role of quantum nuclear motion
Quantum tunneling refers to the general physical phenomenon where a particle tunnels through a barrier that it cannot overcome, i.e. it takes a shortcut. Tunneling plays an essential role in several physical, chemical, and biological phenomena, such as radioactive decay or the manifestation of large kinetic isotope effects in chemicals of enzymatic reactions. It also has important applications for modern devices such as the semiconductor tunnel diodes or the Scanning Tunneling Microscope (STM).
"Quantum tunneling occurs when light atoms, such as hydrogen, are involved. Hydrogen transfer reactions and the manipulation of carbon-hydrogen bonds feature prominently in a wide range of biomolecular systems," said Grant.
According to Grant, there are still many fundamental questions regarding the feature of hydrogen tunneling that the scientific community would like to probe, such as: what is the catalytic effect - if any - of tunneling? This is currently being addressed by researcher Theo Zelleke in his PhD thesis.
The results of the study will eventually help to understand the mechanism of tunneling in enzymes and find out if certain enzymes incorporate subtle nuclear quantum effects into their catalytic cycle.
The sum of knowledge regarding scientific comprehension of fundamental processes in biology is great, but far from complete; despite it having wider implications in a range of applications. This includes pharmaceutical drug development, drug metabolism in predictive medicine, artificial protein synthesis, and biomimicry (a new discipline on innovation inspired by nature).
"Clearly, many biological processes involve proton transfer where, in principle, quantum tunneling could be important. This phenomenon, however, is very subtle in that small changes make big effects," Grant said.
"It remains to be seen if nature exploited tunneling in evolution. If so, could similar mechanisms be used in pharmaceutical drug development? Our research is really about increasing our basic knowledge of how enzymes work. Consideration of nuclear quantum effects can play a part in this, complementing the classic barrier model we're used to working with."
A version of this story first appeared on the PRACE newsletter 8.