Coarse-grained model for simulation of RNA three-dimensional structures

Abstract

The accurate prediction of an RNA's three-dimensional structure from its "primary structure" will have a tremendous influence on the experimental design and its interpretation and ultimately our understanding of the many functions of RNA. This paper presents a general coarse-grained (CG) potential for modeling RNA 3-D structures. Each nucleotide is represented by five pseudo atoms, two for the backbone (one for the phosphate and another for the sugar) and three for the base to represent base-stacking interactions. The CG potential has been parametrized from statistical analysis of 688 RNA experimental structures. Molecular dynamic simulations of 15 RNA molecules with the length of 12-27 nucleotides have been performed using the CG potential, with performance comparable to that from all-atom simulations. For ~75% of systems tested, simulated annealing led to native-like structures at least once out of multiple repeated runs. Furthermore, with weak distance restraints based on the knowledge of three to five canonical Watson-Crick pairs, all 15 RNAs tested are successfully folded to within 6.5 Å of native structures using the CG potential and simulated annealing. The results reveal that with a limited secondary structure model the current CG potential can reliably predict the 3-D structures for small RNA molecules. We also explored an all-atom force field to construct atomic structures from the CG simulations.

Figure 1

(a) Schematic representation of the CG model for RNA. Phosphate and sugar are represented as one CG particle. The bases A, G, C, and U are represented as three CG particles for each. (b) The components of each CG base. The base is divided by the red dash line. (c) Schematic representation of all-atom RNA backbone.

Figure 2

Superposition of final snapshot from 10 ns CG simulations (colored green) and native structure (colored blue). The backbones are represented as thick sticks and the bases are shown as lines. (a) Superposition of RNA with 12 canonical Watson-Crick base pairs (PDB ID: 1QCU). (b) Superposition of the frameshifting RNA pesudoknot from beet western yellow virus (PDB ID: 1L2X), a single chain with coaxial helices connected by two loops. (c) Superposition of 12 nt dsRNA with 5-bp internal loop (PDB ID: 1LNT).

Figure 3

(a) Comparison of all-atom RMSDs for the structures 1ZIH, 353D and 1DQF during the 100 ns simulated annealing simulations. The simulation temperature was increased to 1,000k within the beginning 2,000 steps and then cooled down to room temperature 298k. The RMSDs were calculated using all of the CG atoms. The figures show how the RNA molecules fold toward to their native structures. (b) Snapshots taken from simulated annealing of 1ZIH. (c) The superposition of final conformation (colored green) and native structure (colored blue) of GCCA tetraloop after 20 ns full-atom MD refinement. The backbone is represented as a ribbon and the base-stacking unit in tetraloop is shown as sticks. (d) Snapshots taken from simulated annealing simulation of 353D.