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Title: Molecular dynamics simulations of nucleotide translocation through α-hemolysin nanopores
Author: Martin, H. S. C.
ISNI:       0000 0004 2729 4168
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2011
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available