Molecular dynamics simulations of nucleotide translocation through α-hemolysin nanopores.
Doctoral thesis, UCL (University College London).
The translocation of polynucleotides through transmembrane protein pores is a fundamental biological process with important medical and biotechnological relevance. The complex translocation process is influenced by a range of factors including the diameter and inner surface of the pore, the secondary structure of the polymer, and the interactions between the polymer and protein. Computer simulations are an invaluable means to investigate microscopic systems and thereby provide a unique, atomistic perspective of important states and processes. This thesis explores how two molecular dynamics methodologies can simulate the translocation of nucleotides through the nanopore α-hemolysin. In the first methodology, non-equilibrium constant velocity-steered simulations are combined with Jarzynski's identity to derive the free energy profiles for the passage of a polynucleotide molecule through the pore. In the second methodology, the free energy profiles are calculated from a biasing force which varies in response to energy barriers encountered during the simulation. Both approaches are used to explain the experimentally observed differences in translocation time through the nanopore between polyadenosine and polydeoxycytidine. In addition to polynucleotides, the study also investigates single nucleotide translocation. Together, the simulations highlight the role of molecular interactions between the nucleic acid molecules and the protein pore. In particular, we find that specific residues of the protein pore dominate the translocation. The unique data set helps assess two methodologies to simulate a system of considerable size and complexity.
|Title:||Molecular dynamics simulations of nucleotide translocation through α-hemolysin nanopores|
|Open access status:||An open access version is available from UCL Discovery|
|Additional information:||Pages 128-137: Reproduced with permission from the Journal of the American Chemical Society, 129(31):9640-9649, 2007. Copyright 2007 American Chemical Society. This article can be found at http://pubs.acs.org/doi/abs/10.1021/ja0689029. Page 139: Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. Page 140: Image reproduced by permission of Stefan Howorka and The Royal Society of Chemistry from Soft Matter, 2009, 5, 613-621 DOI:10.1039/B815065F. Page 141: Reproduced with permission from the Journal of Chemical Theory and Computation, 5(8):2135-2148, 2009. Copyright 2009 American Chemical Society.|
|UCL classification:||UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry|
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