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.

Structural Articulation of Biochemical Reactions Using Restrained Geometries and Topology Switching

“…It can rapidly predict structures for reactant, intermediate, or product states starting from an experimental or modeled structure in any one of these states. Covalent bonds provide a strong restraint for the conformational variability of substrates and products and could be a basis for reasonable structure prediction. , For example, starting from just a product state conformation of the enzyme, a product molecule could be docked into the active site, and the reverse biochemical reaction could be modeled using RGATS to obtain a reasonable structural model for the substrate–enzyme complex reactant state. As the RGATS strategy is implemented through simple topology file modifications and standard geometric restraints in existing MM simulation programs, the human learning curve costs for modeling chemical reaction pathways are significantly lowered.…”

Modeling pK Shift in DNA Triplexes Containing Locked Nucleic Acids

“…The so-assigned atom types and dihedral terms for oxymethylene atoms introduce artifacts in backbone torsion γ (O5′−C5′−C4′−C6′), as previously discussed in a free energy study on LNA. 44 Thus, a systematic optimization is required for LNA parameters.…”

“…To evaluate the effect of LNA sugar on p K of cytidine, we reparameterized LNA force field parameters based on the general CHARMM strategy. − The current LNA parameters by Pande and Nilsson were based on analogs. The so-assigned atom types and dihedral terms for oxymethylene atoms introduce artifacts in backbone torsion γ (O5′–C5′–C4′–C6′), as previously discussed in a free energy study on LNA . Thus, a systematic optimization is required for LNA parameters.…”

Simulating Biomolecules: Festschrift to commemorate the 60th birthday of Charles L. Brooks III

“…[3] In the contribution from Nilsson and co-workers, free energy methods are used to characterise the free energy change between locked nucleic acid and DNA nucleosides. [4] Mohammadiarani and Vashisth use, in their study, metadynamics to investigate the folding thermodynamics of an insulin peptide mimetic, which they discover has a strong helical propensity. [5] Okamoto and Ichiye present studies on proteins under high pressure, [6] [7] Dominy investigates the effect from metal ion in tumor Endothelial Marker 8 and Anthrax Protective Antigen, [8] and Pettitt explores phage-like packing structures with mean field sequence dependence.…”

“…Dickson and colleagues, in their study, use a Karanicolas‐Brooks Gō‐like model to examine the dynamics of the enzyme β‐glucuronidase using an umbrella sampling method . In the contribution from Nilsson and co‐workers, free energy methods are used to characterise the free energy change between locked nucleic acid and DNA nucleosides . Mohammadiarani and Vashisth use, in their study, metadynamics to investigate the folding thermodynamics of an insulin peptide mimetic, which they discover has a strong helical propensity .…”