Accelerated molecular discovery

Combining physical, biological and data sciences
for insight and molecular discovery

Algorithmic designs to predict new classes of antimicrobials

Infections will be the deadliest diseases unless we act now. Up to 700,000 people die every year of drug-resistant infections, increasing to 10 million by 2050 and costing the economy a total of 100 trillion USD. To avoid “being cast back into the dark ages of medicine,” there is an urgent need backed by UK government strategy to conserve existing antibiotics and discover new ones.

Combining techniques at the interface between data, physical and biological sciences is a powerful tool to design new molecules and materials. Biomolecular simulation gives a detailed understanding of how molecules interact with targets, and data science can find patterns and design rules in large datasets. Together with biophysical experiments, these techniques create a feedback cycle that leads to quick insight and accelerated discovery.

In this context, we are exploring the rational design of new classes of antimicrobials. Our initial target is to mine protein sequences for short antimicrobial motifs that kill bacteria, but leave human cells unaffected. We seek to demonstrate how experimental and computer-generated datasets can be harvested to reveal features that inform new design concepts. We are developing new analysis and visualisation tools. We are revealing new molecular modes of action by which proteins interact and permeate cell membranes. The aim is to design new antimicrobial compounds unrelated to others.

Discovery loop

Next-generation materials modelling at the atomic and molecular scale

Despite steady advances in computational power, tradeoffs exist between completeness of the description of interactions and the time and length scales that are accessible for sampling. Thus, simulation of complex systems is achieved using highly simplified models, which may not capture the fundamental interactions responsible for emergent behavior. This is particularly acute in (but not unique to) bimolecular simulation where the pharmaceutical industry is seeking new innovations in primary methods.

We have developed a fundamentally new strategy for efficient, predictive models at the molecular scale with complete electronic responses, reduced reliance on empirical input from the condensed phase and the prospects for vastly improved transferability and predictive value. The resulting level of completeness in physical description enables isolated molecule properties to define model parameters, thereby eliminating fitting to condensed phase data. Thus, the framework provides a physical and intuitive basis for predictive, next-generation simulation.

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Publications

A. Pyne, M.P. Pfeil, I. Bennett, J. Ravi, P. Iavicoli, B. Lamarre, A. Roethke, J. Crain
Engineering monolayer poration for rapid exfoliation of microbial membranes
Chemical Science 8(2), 1105-1115, 2017.

G. Henihan, H. Schulze, D.K. Corrigan, G. Giraud, J.G. Terry, A. Hardie, J. Crain
Label- and amplification-free electrochemical detection of bacterial ribosomal RNA
Biosensors and Bioelectronics 81, 487-494, 2016.

F.S. Cipcigan, V.P. Sokhan, J. Crain, G.J. Martyna
Electronic coarse graining enhances the predictive power of molecular simulation allowing challenges in water physics to be addressed
Journal of Computational Physics 326, 222-233, 2016.

V.P. Sokhan, A. Jones, F.S. Cipcigan, G.J. Martyna, J. Crain
Molecular-scale remnants of the liquid-gas transition in supercritical polar fluids
Physical Review Letters 115(11), 117801, 2015.

A. Jones, F. Cipcigan, V.P. Sokhan, J. Crain, G.J. Martyna
Electronically coarse-grained model for water
Physical Review Letters 110(22), 227801, 2013.

L. Ryan, B. Lamarre, T. Diu, J. Ravi, P.J. Judge, A. Temple, M. Carr, E. Cerasoli, J. Crain, M.G. Ryadnov
Anti-antimicrobial Peptides. Folding-mediated Host Defense Antagonists
Journal of Biological Chemistry 288(28), 20162-20172, 2013.

P.D. Rakowska, H. Jiang, S. Ray, A. Pyne, B. Lamarre, M. Carr, P.J. Judge et al.
Nanoscale imaging reveals laterally expanding antimicrobial pores in lipid bilayers
Proceedings of the National Academy of Sciences 110(22), 8918-8923, 2013.

S.N. Syed, H. Schulze, D. Macdonald, J. Crain, A.R. Mount, T.T. Bachmann
Cyclic denaturation and renaturation of double-stranded DNA by redox-state switching of DNA intercalators
Journal of the American Chemical Society 135(14), 5399-5407, 2013.

D.K. Corrigan, H. Schulze, G. Henihan, I. Ciani, G. Giraud, J.G. Terry, J. Crain
Impedimetric detection of single-stranded PCR products derived from methicillin resistant Staphylococcus aureus (MRSA) isolates
Biosensors and Bioelectronics 34(1), 178-184, 2012.

V.P. Sokhan, A.P. Jones, F.S. Cipcigan, J. Crain, G.J. Martyna
Signature properties of water: Their molecular electronic origins
Proceedings of the National Academy of Sciences 112(20), 6341-6346, 2015.

Ask the experts

Flaviu Cipcigan

Flaviu Cipcigan

Jason Crain

Jason Crain

Glenn Martyna

Glenn Martyna
IBM T.J. Watson Research Center