Development of Coarse-Grained Martini Model for Nucleic Acid Structures

Abstract

Molecular modeling has been extensively used to describe various properties of biological systems with all-atom detail. However, its application has been limited by the size of the system and accessible simulation times. During the past few years, the coarse-grained Martini model has been developed for biomolecular systems, allowing larger scale simulations not affordable by all atom models1. Despite significant progress in modeling biomolecules such as lipids and proteins, Martini has not been properly parameterized yet to describe nucleic acids. A reliable description of nucleic acids would enable studies of a range of important problems involving DNA, RNA, and their complexes with proteins and lipids. One example of the latter is lipid nanoparticles (LNPs). LNPs are effective delivery systems for transferring small interfering RNA (siRNA) into the cell, where they can induce silencing of a target gene2. Lipid-nucleic acid interactions and their energetics are important in the gene delivery step in which nucleic acid has to be transferred through the cell membrane into the target cell and released. We have performed extensive umbrella sampling simulations to obtain benchmark PMF profiles of four DNA/RNA nucleobase interactions with phospholipid bilayers using the AMBER and CHARMM force fields and a set of four different lipids. Based on these results, we are developing Martini parameters for these nucleobases and extending the simulations to larger systems including DNA/RNA strands. The results of this work will be useful in studies of DNA-binding proteins and lipoplexes, DNA-sequencing technology, the mechanism of viral protein RNA polymerase, and drug delivery systems.1. Marrink et al., Chem. Soc. Rev. 42, 6801-6822, 2013.2. Semple et al., Nature Biotech. 28, 172-U18, 2010.