Featured publication: multiscale simulation to predict efficiency of β-lactamase inhibition

Growing resistance to antibiotics is a major threat to human health and there is an urgent need to develop new antibiotics or find new ways to keep existing antibiotics effective.  β-lactamases are a class of enzymes that have evolved to break down penicillin-type antibiotics, leading to resistance. One method to avoid this is to administer a β-lactamase inhibitor as a resistance blocker. Clavulanic acid is one such example and is often combined with amoxicillin to form the drug commonly known as co-amoxiclav. In a recent paper published in Biochemistry, van der Kamp and co-workers have used combined quantum mechanics / molecular mechanics (QM/MM) methods to investigate how clavulanic acid can be broken down by different β-lactamases. TEM-1 and KPC-2 are clinically important enzymes that exhibit different susceptibilities to inhibition by clavulanic acid, with KPC-2 effectively resistant to inhibition by clavulanic acid.

QM/MM simulations were carried in AMBER with the semiempirical SCC-DFTB method used for the QM region and the MM region described by AMBER’s ff14SB force field. Complete two-dimensional free energy surfaces were then obtained by QM/MM umbrella sampling (US) simulations along two reaction coordinates: one to describe the proton transfer and one to describe the nucleophilic attack involved in deacylation step of the reaction.   The weighted-histogram analysis method (WHAM) was used to generate the free energy surfaces and the minimum free energy path (MEP) on the surfaces was determined using the minimum energy pathway analysis for energy landscapes (MEPSA) software. The results show that the QM/MM screening protocol is reliable in discriminating the inhibitory activity of different covalent complexes in class A β-lactamases and can differentiate enzymes for which clavulanic acid is an effective inhibitor (TEM-1) from those for which it is not (KPC-2). Such screening techniques will prove to be useful in the development of new strategies to overcome antibiotic resistance.

Press release:


Full paper:

‘Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition’ by Rubén A. Fritz, Jans H. Alzate-Morales, James Spencer, Adrian J. Mulholland and Marc W. van der Kamp in Biochemistry.

Featured publication: Specific cardiolipin–SecY interactions are required for proton-motive force stimulation of protein secretion

In a recent publication in PNAS, Corey et al (Collinson Group,  School of Biochemistry, University of Bristol) work on the bacterial form of the general secretion system – aka the SecY machinery. This complex carries out the bulk of pre-protein secretion at the bacterial plasma membrane, powered by both ATP and the proton-motive force (PMF). They were interested in the interaction of SecY with the energetically-important cardiolipin (CL) molecule. CL is thought to be involved in many different bioenergetics processes, and has been previously implicated in SecY activity.

To approach this problem, they coupled the high predictive power of coarse-grained (CG) molecular dynamics (MD) with experimental analyses. Considerable speed up on atomistic simulation can be achieved using CG force fields, such as the Martini force field for biomolecules. By reducing the degrees of freedom of a system, it is possible to achieve sampling orders of magnitude faster than atomistic simulation – driven primarily by an increase in permissible MD step size, a reduction in interactions to compute per step and a smoothing of the energy landscape.

The CG data revealed two distinct CL binding sites on the SecY surface, which they were able to validate using native mass spectrometry (nMS), with Dr Argyris Politis at King’s College London, and FRET-based analysis on carefully designed variants of SecY.

Cardiolipin bound to SecY.

They then used these knockout variants to more deeply understand the importance of the SecY-CL interactions. Using a range of biochemical assays, they reveal that the specific interaction of CL at these sites is responsible for the previously-recorded heightened activity of SecY. Moreover, they establish a hitherto unknown role for CL in the PMF-driven activity of SecY. This is the first direct evidence of CL acting directly with the PMF in any bioenergetic system.

BcompB Seminar: Dr Simon Bennie

Improving the teaching of enzymology using VR

17/07/18 Chemistry LT4 2pm

Dr Simon Bennie from the Glowacki Group will talk about the introduction of multi-user VR technology into Chemistry undergraduate teaching labs. This work was recently awarded the University Educational Initiative Award 2018. Interactive MD simulations in VR have recently been highlighted in the News on Bristol University’s website, Chemistry World and also by the New York Times. There will be the opportunity to try out the VR framework after the seminar.

Featured publication: interactive molecular dynamics using a multi-user virtual reality framework

Tangible physical models have an important place in the history of chemistry and biochemistry. Three-dimensional (3D) molecular models have been used as conceptual and educational tools dating back to at least von Hofmann in the 1860s. Now we are able to further our understanding by interacting with molecules in real time as they move using virtual reality (VR) technology. The multi-user VR framework has been developed by a joint team of computer science and chemistry researchers at the University of Bristol, in collaboration with developers at Interactive Scientific and Oracle Corporation, have used Oracle’s public cloud infrastructure to combine real-time molecular simulations with the latest VR technology.

The movie below shows a researcher taking hold of a fully solvated benzylpenicillin ligand and interactively guiding it to dock it within the active site of the TEM-1 β-lactamase enzyme (with both molecules fully flexible and dynamic) and generate the correct binding mode. The simulations make use of a plug-in that communicates with the GPU-accelerated molecular simulation package OpenMM via PLUMED, allowing models of the type used for conventional MD simulations to be used directly within the VR framework. Generating a benzylpenicillin docking pathway would be very difficult just using standard computer algorithms, but as can be seen in the movie, the VR framework is intuitive and easy to control, enabling the researcher to generate a physically meaningful path. Anybody wishing to try out the tasks described in the paper can download the software at https://isci.itch.io/nsb-imd, and launch their own cloud-hosted session.

Press release:


Full Paper:

Sampling molecular conformations and dynamics in a multi-user virtual reality framework‘ by Michael O’Connor, Helen M. Deeks, Edward Dawn, Oussama Metatla, Anne Roudaut, Matthew Sutton, Becca Rose Glowacki, Rebecca Sage, Philip Tew, Mark Wonnacott, Phil Bates, Adrian J. Mulholland and David R. Glowacki in Science Advances.