Oritatami: A Computational Model for Molecular Co-Transcriptional Folding

We introduce and study the computational power of Oritatami, a theoretical model that explores greedy molecular folding, whereby a molecular strand begins to fold before its production is complete. This model is inspired by our recent experimental work demonstrating the construction of shapes at the nanoscale from RNA, where strands of RNA fold into programmable shapes during their transcription from an engineered sequence of synthetic DNA. In the model of Oritatami, we explore the process of folding a single-strand bit by bit in such a way that the final fold emerges as a space-time diagram of computation. One major requirement in order to compute within this model is the ability to program a single sequence to fold into different shapes dependent on the state of the surrounding inputs. Another challenge is to embed all of the computing components within a contiguous strand, and in such a way that different fold patterns of the same strand perform different functions of computation. Here, we introduce general design techniques to solve these challenges in the Oritatami model. Our main result in this direction is the demonstration of a periodic Oritatami system that folds upon itself algorithmically into a prescribed set of shapes, depending on its current local environment, and whose final folding displays the sequence of binary integers from 0 to N = 2 k − 1 with a seed of size O ( k ) . We prove that designing Oritatami is NP-hard in the number of possible local environments for the folding. Nevertheless, we provide an efficient algorithm, linear in the length of the sequence, that solves the Oritatami design problem when the number of local environments is a small fixed constant. This shows that this problem is in fact fixed parameter tractable (FPT) and can thus be solved in practice efficiently. We hope that the numerous structural strategies employed in Oritatami enabling computation will inspire new architectures for computing in RNA that take advantage of the rapid kinetic-folding of RNA.

A Common Variant of ASAP1 Is Associated with Tuberculosis Susceptibility in the Han Chinese Population

Background. ASAP1 (also known as AMAP1 or DDEF1) encodes an Arf GTPase-activating protein (Arf GAP), a multifunctional scaffold protein that induces hydrolysis of GTP bound to the ADP-ribosylation factor (Arf) family GTP-binding proteins. Reduction of ASAP1 expression in vitro was related to suppression of cell migration and invasiveness. The genetic variant rs4733781 of the ASAP1 gene was revealed as a significant locus for tuberculosis (TB) susceptibility, but the results still need to be validated. Methods. Blood samples from a total of 1914 active TB and healthy controls (HC) were collected to evaluate rs4733781 and the risk of TB. Meanwhile, a total of 48 noninfected HC, latent TB-infected (LTBI) controls, and active TB were collected to assay ASAP1 expression difference among the three groups. The QuantiFERON-TB Gold In-Tube was adopted to identify noninfected HC and LTBI. Results. The genetic variant of rs4733781 was found to be significantly associated with TB, and the A allele of rs4733781 (C>A) was 0.38 and 0.43 among TB cases and HC, respectively (P=0.0035). Meanwhile, the peripheral blood monocyte RNA fold changes for the ASAP1 gene among the 16 HC, 16 LTBI, and 16 active TB were 1.088±0.4919, 2.237±0.6505, and 10.12±10.98 (F=9.559, P=0.0003), respectively, and the expression of ASAP1 was increased by 2.06-fold (P<0.0001) and 9.30-fold (P<0.0052) for LTBI and active TB, when compared to the HC. Conclusions. Our data indicated that the A allele of rs4733781 for the ASAP1 gene was in association with a decreased risk of TB. But not only that, the overexpression of the ASAP1 gene among LTBI and TB was related to the progression of TB, which further implies that the expression of ASAP1 would be a potential biomarker for LTBI and TB diagnoses.

Structures of two aptamers with differing ligand specificity reveal ruggedness in the functional landscape of RNA

Two classes of riboswitches related to the ykkC guanidine-I riboswitch bind phosphoribosyl pyrophosphate (PRPP) and guanosine tetraphosphate (ppGpp). Here we report the co-crystal structure of the PRPP aptamer and its ligand. We also report the structure of the G96A point mutant that prefers ppGpp over PRPP with a dramatic 40,000-fold switch in specificity. The ends of the aptamer form a helix that is not present in the guanidine aptamer and is involved in the expression platform. In the mutant, the base of ppGpp replaces G96 in three-dimensional space. This disrupts the S-turn, which is a primary structural feature of the ykkC RNA motif. These dramatic differences in ligand specificity are achieved with minimal mutations. ykkC aptamers are therefore a prime example of an RNA fold with a rugged fitness landscape. The ease with which the ykkC aptamer acquires new specificity represents a striking case of evolvability in RNA.