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Dynamics and catalysis in enzymes

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  • Full or part time
    Prof A J Mulholland
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

The project:
TMCS is an EPSRC Centre for Doctoral Training operated by the Universities of Oxford, Bristol and Southampton.

In year one you will be based in Oxford with a cohort of around 12–15 other TMCS students, and will receive in-depth training in fundamental theory, software development, and chemical applications, delivered by academics from all three Universities. Successful completion of the year-one program leads to the award of an Oxford MSc, and progression to the 3-year PhD project based in Bristol, and detailed below.

Dynamics and catalysis in enzymes

Enzymes are superb natural catalysts, but the exact causes of their catalytic power remain hotly debated. Design of protein catalysts with efficiency comparable to natural enzymes remains a distant dream; if we could design protein catalysts as powerful as enzymes, the range of applications in synthesis, ‘green’ chemistry and biotechnology would be huge.

Perhaps the most controversial question in current enzymology is the possible role of protein dynamics in catalysis, particularly for enzyme reactions involving quantum tunnelling (see our Perspective, Glowacki et al., Nature Chemistry doi:10.1038/nchem.1244, 2012). The essential question is: how do motions of an enzyme contribute to its catalytic activity? This project will investigate the role of protein dynamics in enzyme catalysis.

Far from being an esoteric phenomenon in biology, quantum tunnelling is an important factor in many enzymes (Masgrau et al. Science 2006). Many enzyme-catalysed reactions show KIEs with complex temperature dependence, which cannot be explained by simple (e.g. single barrier) models. It has been proposed that protein dynamics are crucial in ‘driving’ reactions. This question has been examined by experimental and theoretical analysis of ‘heavy’, completely isotopically substituted enzymes (Luk et al. PNAS 2013).

In this project, we will develop simulation methods for direct calculation of these effects by quantum dynamical molecular simulations. These will apply ring polymer molecular dynamics techniques based on the path integral formalism for direct treatment of quantum effects (Boekelhide et al. PNAS 2011), applicable even for highly delocalized systems for which reaction path based methods may fail.

We will develop and use empirical valence bond (EVB) potential energy functions, parameterized against our high-level QM/MM calculations, for accurate atomistic representation of the reacting enzyme systems. We will directly calculate the contribution of quantum effects using coupled thermodynamic integration simulations. Uniquely, this will give directly the contribution of quantum effects to the barrier at all temperatures studied.

We will apply these combined methods to study reactions catalysed by several important enzymes. The project will involve a variety of simulation techniques, including molecular dynamics simulations of protein complexes to examine conformational effects, and analysis of protein motions during all stages of the catalytic cycle, providing a broad training.

How to apply:
Please make an online application for this PhD position at
For further details please see

Candidate requirements:
UK or EU citizen fully funded
Successful applicants to TMCS typically hold a first class honours degree (or equivalent) in Chemistry or a closely related discipline.

Project queries: Adrian Mulholland [email protected]
TMCS queries: [email protected]

Deadline for applications can be found on the TMCS webpage:

Funding Notes

Full funding of fees and stipend for 4 years.
Standard EPSRC stipend (currently £14,057)

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