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Investigation of biologically relevant proteins using the combination of magnetic tweezers experiments and a novel molecular dynamics method

Hovan, Ladislav; (2020) Investigation of biologically relevant proteins using the combination of magnetic tweezers experiments and a novel molecular dynamics method. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

We have developed a novel metric for the path collective variables. This metric measures the distance from reference configurations using a combination of simple collective variables, with their contributions optimised for maximising the path entropy. We have called this approach COMet-Path (computational optimisation of a metric for path collective variables). We have validated it using transitions between the conformational minima of trialanine peptide. To compare it to earlier RMSD metric, we have also applied it to the computation of the absolute binding free energy for the Dasatinib binding to c-Src kinase, and we have obtained good agreement with our previous results. We have then applied this approach also to the problem of predicting absolute binding free energies. As a test system, we used a set of epoxide hydrolase inhibitors. We have developed a technique that allows us to predict their binding free energy values with high accuracy at low computational cost. It has also allowed us to understand more about which collective variables and optimisation settings offer better results for difficult problems. In the next part, we investigated the WW domain of PQBP1, where a Y65C single point mutation is responsible for the emergence of the Golabi-Ito-Hall syndrome. Through the use of magnetic tweezers, we showed that the mutant exhibits unexpected behaviour and sensitivity to redox conditions, unlike the wild type. We have also attempted to model the behaviour of these domains using several molecular dynamics approaches, including COMet-Path. Finally, we applied magnetic tweezers also to the problem of the binding of talin to integrin. We have been able to determine the geometry of this interaction and were able to quantify the force required to break it, along with the unfolding force of the individual components of the talin head domain.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigation of biologically relevant proteins using the combination of magnetic tweezers experiments and a novel molecular dynamics method
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. - Some third party copyright material has been removed from this e-thesis.
Keywords: molecular dynamics, enhanced sampling, path collective variables, magnetic tweezers, golabi-ito-hall syndrome, epoxide hydrolase, talin, integrin
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10098060
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