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RNA macromolecules, like proteins, fold to assume shapes that are intimately connected to their broadly recognized biological functions; however, because of their high charge and dynamic nature, RNA structures are far more challenging to determine. We introduce an approach that exploits the high brilliance of x-ray free-electron laser sources to reveal the formation and ready identification of angstrom-scale features in structured and unstructured RNAs. Previously unrecognized structural signatures of RNA secondary and tertiary structures are identified through wide-angle solution scattering experiments. With millisecond time resolution, we observe an RNA fold from a dynamically varying single strand through a base-paired intermediate to assume a triple-helix conformation. While the backbone orchestrates the folding, the final structure is locked in by base stacking. This method may help to rapidly characterize and identify structural elements in nucleic acids in both equilibrium and time-resolved experiments.
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Nucleic acid folding simulations using a physics-based atomistic free energy model
Performing full-resolution atomistic simulations of nucleic acid folding has remained a challenge for biomolecular modeling. Understanding how nucleic acids fold and how they transition between different folded structures as they unfold and refold has important implications for biology. This paper reports a theoretical model and computer simulation of the ab initio folding of DNA inverted repeat sequences. The formulation is based on an all-atom conformational model of the sugar-phosphate backbone via chain closure, and it incorporates three major molecular-level driving forces—base stacking, counterion-induced backbone self-interactions, and base pairing—via separate analytical theories designed to capture and reproduce the effects of the solvent without requiring explicit water and ions in the simulation. To accelerate computational throughput, a mixed numerical/analytical algorithm for the calculation of the backbone conformational volume is incorporated into the Monte Carlo simulation, and special stochastic sampling techniques were employed to achieve the computational efficiency needed to fold nucleic acids from scratch. This paper describes implementation details, benchmark results, and the advantages and technical challenges with this approach.
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- Award ID(s):
- 1664801
- PAR ID:
- 10593488
- Publisher / Repository:
- American Institute of Physics
- Date Published:
- Journal Name:
- The Journal of Chemical Physics
- Volume:
- 156
- Issue:
- 17
- ISSN:
- 0021-9606
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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