Abstract
Modeling structures and functions of large ribonucleic acid (RNAs) especially with complicated topologies is highly challenging due to the inefficiency of large conformational sampling and the presence of complicated tertiary interactions. To address this problem, one highly promising approach is coarse-grained modeling. Here, following an iterative simulated reference state approach to decipher the correlations between different structural parameters, we developed a potent coarse-grained RNA model named as IsRNA1 for RNA studies. Molecular dynamics simulations in the IsRNA1 can predict the native structures of small RNAs from a sequence and fold medium-sized RNAs into near-native tertiary structures with the assistance of secondary structure constraints. A large-scale benchmark test on RNA 3D structure prediction shows that IsRNA1 exhibits improved performance for relatively large RNAs of complicated topologies, such as large stem-loop structures and structures containing long-range tertiary interactions. The advantages of IsRNA1 include the consideration of the correlations between the different structural variables, the appropriate characterization of canonical base-pairing and base-stacking interactions, and the better sampling for the backbone conformations. Moreover, a blind screening protocol was developed based on IsRNA1 to identify good structural models from a pool of candidates without prior knowledge of the native structures.