Computational modeling of protein-ion binding and nucleic acids

Metal ions and nucleic acids are essential for a variety of biological functions. Metal ions play roles in enzyme catalysis, signal transduction and muscle contraction, and the stabilization of protein and nucleic acids structures. Nucleic acids are integral to gene expression and regulation. There are many unsolved questions regarding the function and thermodynamics of metal ions and nucleic acids. Molecular modeling has been an indispensable tool for microscopic understanding of biological processes. While tremendous success has been achieved for the modeling of proteins and organic molecules, it remains challenging to accurate model charged molecules, such as metal ions and nucleic acids. The difficulty mainly arises from the inadequate description of electrostatic interaction and polarization. In this work, accurate models for metal ions and nucleic acids based on AMOEBA polarizable force field were developed. These models along with advanced quantum mechanical methods were then used to study some practical problems. First, the principles underlying Ca²⁺/Mg²⁺ selectivity in ion-binding proteins were studied. It was shown that the Ca²⁺/Mg²⁺ selectivity can be explained by many-body polarization, which depends on the chemistry and geometry of the binding pocket. Second, an existing controversial question regarding the conduction mechanism of potassium channels was resolved by molecular dynamics (MD) simulations with AMOEBA. Contrary to previous beliefs, the conduction operates through nearly ion-saturated states. This mechanism is compatible with almost all existing experimental data. Third, free energy calculation with AMOEBA was used to predict the effect of chemical modifications on the stability of DNA-RNA hybrids, which has implications for the development of gene therapy. Overall, the AMOEBA polarizable force field significantly improves the accuracy for modeling of metal ions and nucleic acids. It is expected that application of polarizable force field will lead to more exciting findings on biological systems.