Open AccessDissertation
Modelling the nanocantilever response to stressed networks of antibiotic binding events
TLDR
The first steps towards a comprehensive theoretical model of stress induction on a nanocantilever operation are reported, focusing on elucidating the chemical and geometric nature of experimentally observed responses to Vancomycin.Abstract:
Antibiotic resistance is a rapidly emerging global health problem as year on year more drugs are rendered ineffective and fewer new antibiotics developed to meet the demand. This is exemplified by Vancomycin, the `antibiotic of last resort' for decades, now facing growing resistance among bacteria. Interest around modifying existing drugs to improve their antibiotic action and stabilise them against resistance is raising the need for detailed understanding of the modes of action of antibiotics. Nanocantilevers provide a complementary method for exploring both the binding process and the mechanical mode of action by which Vancomycin and its derivatives weaken and destroy bacterial cell wall. When functionalised with monolayers of peptides analogous to cell wall precursors the cantilevers measure the build up of surface stresses in-plane, on a surface, representative of the antibacterial interactions in-situ. This thesis reports the first steps towards a comprehensive theoretical model of stress induction on a nanocantilever, focusing on elucidating the chemical and geometric nature of experimentally observed responses to Vancomycin. The chemical origins of stress generation are explored within, using a monolayer of decanethiol as a model system and looking at contributions from both adsorbate-adsorbate and adsorbate-substrate interactions. How those individual molecular contributions combine across the cantilever to produce the eventual deflection is investigated by varying the coverage of Vancomycin binding events across an appropriately functionalised cantilever, using an interaction potential extrapolated from molecular dynamics simulations and a lattice model developed in this thesis to return the corresponding stress and deflection. The elastic response of the beam itself is also examined in some detail, as is the effect of the operating medium on the cantilever's action. All findings provide the first steps to a truly representative, and quantitatively predictive, model of nanocantilever operation and insight into the technology's unique merit in the race to discover a new generation of antibiotics.read more
Citations
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Resonant oscillations of fluid‐loaded struts
TL;DR: In this paper, a simple model is used to describe how radiation damping limits the resonant oscillations of a cantilever or strut, and it is shown that high frequency resonances are heavily damped, regardless of internal dissipation.
References
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TL;DR: The theory of the slipline field is used in this article to solve the problem of stable and non-stressed problems in plane strains in a plane-strain scenario.
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CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
Bernard R. Brooks,Robert E. Bruccoleri,Barry D. Olafson,David J. States,S. Swaminathan,Martin Karplus +5 more
TL;DR: The CHARMM (Chemistry at Harvard Macromolecular Mechanics) as discussed by the authors is a computer program that uses empirical energy functions to model macromolescular systems, and it can read or model build structures, energy minimize them by first- or second-derivative techniques, perform a normal mode or molecular dynamics simulation, and analyze the structural, equilibrium, and dynamic properties determined in these calculations.
Journal ArticleDOI
All-atom empirical potential for molecular modeling and dynamics studies of proteins.
Alexander D. MacKerell,D. Bashford,M. Bellott,Roland L. Dunbrack,Jeffrey D. Evanseck,Martin J. Field,Stefan Fischer,Jiali Gao,H. Guo,S. Ha,Diane Joseph-McCarthy,L. Kuchnir,K. Kuczera,F. T. K. Lau,C. Mattos,Stephen W. Michnick,Thien H. Ngo,D. T. Nguyen,B. Prodhom,W. E. Reiher,Benoît Roux,M. Schlenkrich,Jeremy C. Smith,Roland H. Stote,John E. Straub,Masakatsu Watanabe,J. Wiórkiewicz-Kuczera,D. Yin,Martin Karplus +28 more
TL;DR: The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals.