Parameterizing modified nucleic acids for molecular simulations in the AMBER MD software environment [Article v1.0]

Abstract

Parameterizing modified nucleic acids is a difficult but necessary task for expanding the simulated space of oligonucleotides, including both naturally occurring structures and those with pharmaceutical relevance. In lieu of expensive and difficult chemical synthesis in the laboratory, computer simulations are often performed to make predictions for sequence and structure effects, as well as downstream critical quality attributes. To enable these simulations, modifications have to be parameterized to faithfully represent their effect on nucleotides. This is a non-trivial process, complicated by the fact that it may be the first thing researchers must figure out before they can build their structures and start their initial simulations. To enable these research projects, we created modXNA, a code that assembles pre-parameterized modules of the base, backbone, and sugar, to create bespoke combinations of modifications. In the following tutorial, we provide background on force field parameterization in the Amber software ecosystem and detail the steps necessary to perform parameterization of modified nucleic acids using modXNA.