Linking experiment to theory: Quantum entanglement during enzyme catalysis

Physicists generally describe the world around them using one of two different models: classical Newtonian mechanics and quantum mechanics. While Newton developed his theory to describe the motion of the planets, quantum mechanics, due to it's greater complexity, is typically only used to describe systems of a few atoms or less. Despite this, quantum mechanics remains an exciting area of research, with its application leading to recent breakthroughs in teleportation and information theory. Biologists have often ignored quantum mechanics, yet it is now becoming evident that quantum mechanical tunnelling plays a significant role during simple biological electron and hydrogen transfer reactions. During these reactions, the wave/particle duality of the transferred electron or hydrogen allows its position to become delocalised (smeared out over space), thus affecting the way the reaction proceeds. An even stranger consequence of quantum mechanics is superposition and entanglement, where the quantum states of two or more distant objects are linked. The proposed research aims to utilise methods we have developed while investigating electron and hydrogen tunnelling reactions to determine whether other quantum mechanical phenomena influence biology processes. Specifically, this research aims to look for evidence of entanglement of different substrate molecules in the active sites of enzymes such as DNA polymerase - an idea that has recently emerged from studies of quantum search algorithms. DNA - 'the molecule of life' - is a polymer of four different nucleotide monomers (dNTPs), denoted A, T, C and G. DNA replication, the method by which living organisms copy their DNA prior to cell division, is the basis for biological inheritance. During replication, each strand of the double-stranded DNA helix can act as a template for the reproduction of another strand of DNA. This replication is catalysed by DNA polymerase, an enzyme that once bound to a section of single stranded DNA template, produces double-stranded DNA by moving along the template strand adding the required dNTP, one at a time. As only one dNTP substrate can bind at a time, it should take four attempts for DNA polymerase to find the correct dNTP (A, T, C or G) during each step of replication. However, in a quantum mechanical world, it is theoretically possible that two or more dNTPs could become entangled and simultaneously superimposed within the active site of DNA polymerase. If this is the case, the enzyme could pre-select the correct substrate without having to perform a blind search for the correct dNTP. This research aims to use a combination of experimental enzymology and computational/theoretical chemistry to determine whether such an entanglement of substrates is possible. This approach can then be extended to investigate many other biologically important enzymes that act on multiple substrates. Further, as mutations are caused by errors in DNA replication due to occasional DNA polymerase infidelity, a greater understanding of how this enzyme distinguishes between its four dNTP substrates could lead to preventative treatments of aging and cancer. Additionally, if quantum entanglement plays an observable role during catalysis, this would demonstrate that coherent quantum states can have 'useful' lifetimes - an important question in theoretical physics and particularly in the emerging field of quantum computing.

Enzymes are often unrivaled catalysts with high substrate specificity. This work will test the unconventional hypothesis that enzymes can enhance both their specificity and catalytic efficiency by exploiting quantum mechanical entanglement. The fundamental mechanism that DNA polymerase - the enzyme family that catalyses DNA replication - uses to select the correct deoxynuclotide (dNTP) substrate from a cellular pool of structurally very similar molecules (dATP, dTTP, dCTP & dGTP) remains unresolved. If the enzyme cannot pre-select the correct dNTP then the reaction will require an inefficient blind search for the correct substrate during each step. As a result, it has been suggested that DNA polymerase might exploit quantum mechanical entanglement to pre-select substrates prior to their binding by collapsing the wavefunction of the correct dNTP within a superposition of multiple dNTPs in the active site. If this is the case, dNTP binding events may be described by Grover's algorithm - a recently proposed quantum search algorithm - that states that it is possible to sample up to four different unsorted states (i.e. dNTP binding events) in a single step. By combining new theory with competitive inhibition studies of the elongation phase of DNA replication with artificial DNA sequences and multi-dimensional competitive enzyme inhibition studies, we will experimentally determine whether DNA polymerase is able to pre-selects dNTPs. If so, the nature of this pre-selection will be probed using methods we have developed to study quantum mechanical electron and hydrogen tunnelling reactions in enzymes. By exploiting the many commercially available DNA polymerase enzymes, it will also be possible to correlate any findings with other properties of the enzyme such as fidelity. If quantum entanglement is found to be a feature of the polymerase-catalysed reaction, then these experiments can be expanded to other enzyme-catalysed where the enzyme acts on multiple substrates.

A proper physical understanding of the catalytic power of enzyme systems is critical for the exploitation of enzyme systems in biotechnology, through rational structure-based redesign and for therapeutic targeting of enzymes to maintain healthy physiological function in humans. While enzymology has been served well by classical transition state theory, it is emerging that quantum mechanics can have a profound effect on certain types of biological reactions. The current focus has been on electron and hydrogen tunnelling reactions, but assessment of the role of other quantum mechanical effects such as entanglement and superposition will also challenge the validity of transition state theory and more general aspects of biological catalysis. If quantum entanglement is found to be a feature of the polymerase-catalysed reaction, this will have several major implications. As mutations are caused by errors in DNA replication due to occasional DNA polymerase infidelity, a greater understanding of how DNA polymerase distinguishes between its four deoxynucleotide substrates could lead to preventative treatments of aging and cancer. Also, if quantum entanglement plays an observable role during catalysis, this would demonstrate that coherent quantum states can have 'useful' lifetimes - an important question in theoretical physics and particularly in the emerging field of quantum computing. More generally, should new physical (and general) descriptions of catalysis emerge from our work, this will have profound effects on how we target enzyme systems therapeutically (drug discovery) and engineer new catalytic properties. This subatomic and molecular description that we seek will serve as a firm foundation upon which to build a more comprehensive scientific understanding of biological catalysis with obvious industrial and medicinal benefits that holds. The beneficiaries of such an improved understanding include: - The health care professionals concerned with the diagnosis, treatment and care of patients through therapeutic intervention using small molecule inhibitors of enzyme systems. - The drug discovery industry. With improved knowledge of how quantum mechanical effects influence catalysis, new approaches to enzyme inhibition can be sought. - The industrial biotechnology sector. Through improved knowledge-based strategies for designing new catalysts - approaches that will need to embrace new theory and recognition of quantum dynamical effects in biological catalysis. It is prudent at this stage to stress the fundamental nature of this research. In order to properly elucidate the influence of quantum mechanical processes such as tunneling and entanglement, it is necessary to conduct (in vitro) experiments on proteins isolated from their biological environment. Therefore, although the beneficiaries should reflect on the immediate results, this research must also be viewed as the foundations of a bottom-up approach to addressing these salient problems. The Fellow (Dr Hay) has recently contributed to several pedagogical texts on quantum mechanical tunneling in enzyme systems (RSC publishing and Springer). He has gained experience in communicating (in both written and oral presentations) complex, physical concepts, and potentially sensitive ideas, to a mixture of medical, life and physical scientists. The Fellow plans to attend the BBSRC's media training course and will endeavour to make his work accessible to non-specialist audience during the course of his fellowship. These types of activities emphasize the commitment of the team to outreach activities and communication to non-specialist audiences. We will continue to make contributions in these areas, particularly in our interactions with the media.