Determination of free energy profiles for the translocation of polynucleotides through α-hemolysin nanopores using non-equilibrium molecular dynamics simulations

Hugh S.C. Martin, Shantenu Jha, Stefan Howorka, Peter V. Coveney

Research output: Contribution to journalArticle

21 Scopus citations


The translocation of polynucleotides through transmembrane protein pores is a fundamental biological process with important technological and medical relevance. The translocation process is complex, and it 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. In this paper, we perform nonequilibrium constant velocitysteered molecular dynamics simulations of nucleic acid molecule translocation through the protein nanopore R-hemolysin and use Jarzynski's identity to determine the associated free energy profiles. With this approach we are able to explain the observed differences in experimental translocation time through the nanopore between polyadenosine and polydeoxycytidine. The translocation of polynucleotides and single nucleotides through R-hemolysin is investigated. These simulations are computationally intensive as they employ models with atomistic level resolution; in addition to their size, these systems are challenging to study due to the time scales of translocation of large asymmetric molecules. Our simulations provide insight into the role of the interactions between the nucleic acid molecules and the protein pore. Mutated protein pores provide confirmation of residue-specific interactions between nucleotides and the protein pore. By harnessing such molecular dynamics simulations, we gain new physicochemical insight into the translocation process.

Original languageEnglish (US)
Pages (from-to)2135-2148
Number of pages14
JournalJournal of Chemical Theory and Computation
Issue number8
Publication statusPublished - Aug 1 2009
Externally publishedYes


All Science Journal Classification (ASJC) codes

  • Computer Science Applications
  • Physical and Theoretical Chemistry

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