Development of a Next-Generation Nucleic Acid Force Field

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PROJECT SUMMARY/ABSTRACT Nucleic acids (NAs) are the major information carrying molecules of life. The ability to use computation to model the structure, dynamic and interactions of DNA and RNA is a key adjunct to experimental study of these biomolecules. For example, pseudouridine-containing mRNA vaccines against Covid-19 are a critical tool in battling the pandemic. DNAs, mRNAs, and miRNAs are targets for a number of antibacterial and antiviral drugs. Design of small molecule drugs binding to nucleic acids in the treatment of cancers and neurodegenerative diseases is one of the hottest topics of current pharmaceutical research. Under this project, we will investigate several key aspects of nucleic acids, and develop the polarizable multipole AMOEBA+ model for simulation of NAs and their interactions. This new force field will be further enhanced via coupling of a machine learning-based potential for local valence features with classical long-range nonbonded interactions. The resulting AMOEBA+NN force field promises chemical accuracy in the calculation of binding for NA systems. Parameters for the AMOEBA+ and AMOEBA+NN potentials will be generated using the new, automated Poltype2 package. Implementation of the force fields into the existing GPU-capable Tinker9 molecular dynamics software will enable state-of-the-art simulation and binding free energy estimation. The applicability of molecular simulation to design of therapeutics is limited by efficiency and accuracy of the calculations. The objective of this proposal is to enable routine, accurate computation of the thermodynamics of binding of small-molecule ligands to NAs. Toward that end, several current systems of biological relevance will be investigated, including binding of metal ions to G-quadruplex structures, fluorogenic ligands with RNA aptamers, novel antibiotic drugs with the FMN riboswitch, and conformational dynamics of the P5abc domain of the Tetrahymena group I ribozyme. The structures and functions of NAs are highly dependent upon their ionic environment. The interplay between RNA local structural dynamics and global/tertiary folding is an intriguing question being addressed experimentally. The ability to simulate these complex energetic effects in the design of novel small molecule drugs and synthetically modified oligonucleotides will be an important growth area for future medical advances. Development of the accurate and transferable next-generation AMOEBA+ and AMOEBA+NN force fields will open new paths toward understand and prediction of the behavior of natural and designed nucleic acid molecules.