title: The free energy of locking a ring: Changing a deoxyribonucleoside to a locked nucleic acid.
abstract: Locked nucleic acid (LNA), a modified nucleoside which contains a bridging group across the ribose ring, improves the stability of DNA/RNA duplexes significantly, and therefore is of interest in biotechnology and gene therapy applications. In this study, we investigate the free energy change between LNA and DNA nucleosides. The transformation requires the breaking of the bridging group across the ribose ring, a problematic transformation in free energy calculations. To address this, we have developed a 3-step (easy to implement) and a 1-step protocol (more efficient, but more complicated to setup), for single and dual topologies in classical molecular dynamics simulations, using the Bennett Acceptance Ratio method to calculate the free energy. We validate the approach on the solvation free energy difference for the nucleosides thymidine, cytosine, and 5-methyl-cytosine. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: You
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Villa
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
mesh_terms: D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D003853:Deoxyribonucleosides / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry*; D012266:Ribose / Q000737:chemistry; D013816:Thermodynamics; D013936:Thymidine / Q000737:chemistry
chemical_list: D003853:Deoxyribonucleosides; D009841:Oligonucleotides; C477371:locked nucleic acid; D012266:Ribose; D003596:Cytosine; D004247:DNA; D013936:Thymidine
keywords: DNA; LNA; MD simulation; bridged ring; free energy perturbation; ribose