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Atomic-accuracy structure prediction of macromolecules is a long-sought goal of computational biophysics. Accurate modeling should be achievable by optimizing a physically realistic energy function but is presently precluded by incomplete sampling of a biopolymers many degrees of freedom. We present herein a working hypothesis, called the stepwise ansatz, for recursively constructing well-packed atomic-detail models in small steps, enumerating several million conformations for each monomer and covering all build-up paths. By implementing the strategy in Rosetta and making use of high-performance computing, we provide first tests of this hypothesis on a benchmark of fifteen RNA loop modeling problems drawn from riboswitches, ribozymes, and the ribosome, including ten cases that were not solvable by prior knowledge based modeling approaches. For each loop problem, this deterministic stepwise assembly (SWA) method either reaches atomic accuracy or exposes flaws in Rosettas all-atom energy function, indicating the resolution of the conformational sampling bottleneck. To our knowledge, SWA is the first enumerative, ab initio build-up method to systematically outperform existing Monte Carlo and knowledge-based methods for 3D structure prediction. As a rigorous experimental test, we have applied SWA to a small RNA motif of previously unknown structure, the C7.2 tetraloop/tetraloop-receptor, and stringently tested this blind prediction with nucleotide-resolution structure mapping data.
Consistently predicting biopolymer structure at atomic resolution from sequence alone remains a difficult problem, even for small sub-segments of large proteins. Such loop prediction challenges, which arise frequently in comparative modeling and prot
We enumerate the number of RNA contact structures according to their genus, i.e. the topological character of their pseudoknots. By using a recently proposed matrix model formulation for the RNA folding problem, we obtain exact results for the simple
We present a novel topological classification of RNA secondary structures with pseudoknots. It is based on the topological genus of the circular diagram associated to the RNA base-pair structure. The genus is a positive integer number, whose value qu
Ribonucleic acid (RNA) is involved in many regulatory and catalytic processes in the cell. The function of any RNA molecule is intimately related with its structure. In-line probing experiments provide valuable structural datasets for a variety of RN
Our work is concerned with the generation and targeted design of RNA, a type of genetic macromolecule that can adopt complex structures which influence their cellular activities and functions. The design of large scale and complex biological structur