If the Current Clique Algorithms are Optimal, so is Valiant's Parser

The CFG recognition problem is: given a context-free grammar $\mathcal{G}$ and a string $w$ of length $n$, decide if $w$ can be obtained from $\mathcal{G}$. This is the most basic parsing question and is a core computer science problem. Valiant's parser from 1975 solves the problem in $O(n^{\omega})$ time, where $\omega<2.373$ is the matrix multiplication exponent. Dozens of parsing algorithms have been proposed over the years, yet Valiant's upper bound remains unbeaten. The best combinatorial algorithms have mildly subcubic $O(n^3/\log^3{n})$ complexity. Lee (JACM'01) provided evidence that fast matrix multiplication is needed for CFG parsing, and that very efficient and practical algorithms might be hard or even impossible to obtain. Lee showed that any algorithm for a more general parsing problem with running time $O(|\mathcal{G}|\cdot n^{3-\varepsilon})$ can be converted into a surprising subcubic algorithm for Boolean Matrix Multiplication. Unfortunately, Lee's hardness result required that the grammar size be $|\mathcal{G}|=\Omega(n^6)$. Nothing was known for the more relevant case of constant size grammars. In this work, we prove that any improvement on Valiant's algorithm, even for constant size grammars, either in terms of runtime or by avoiding the inefficiencies of fast matrix multiplication, would imply a breakthrough algorithm for the $k$-Clique problem: given a graph on $n$ nodes, decide if there are $k$ that form a clique. Besides classifying the complexity of a fundamental problem, our reduction has led us to similar lower bounds for more modern and well-studied cubic time problems for which faster algorithms are highly desirable in practice: RNA Folding, a central problem in computational biology, and Dyck Language Edit Distance, answering an open question of Saha (FOCS'14)

Bayesian estimates of free energies from nonequilibrium work data in the presence of instrument noise

The Jarzynski equality and the fluctuation theorem relate equilibrium free energy differences to non-equilibrium measurements of the work. These relations extend to single-molecule experiments that have probed the finite-time thermodynamics of proteins and nucleic acids. The effects of experimental error and instrument noise have not previously been considered. Here, we present a Bayesian formalism for estimating free-energy changes from non-equilibrium work measurements that compensates for instrument noise and combines data from multiple driving protocols. We reanalyze a recent set of experiments in which a single RNA hairpin is unfolded and refolded using optical tweezers at three different rates. Interestingly, the fastest and farthest-from-equilibrium measurements contain the least instrumental noise, and therefore provide a more accurate estimate of the free energies than a few slow, more noisy, near-equilibrium measurements. The methods we propose here will extend the scope of single-molecule experiments; they can be used in the analysis of data from measurements with AFM, optical, and magnetic tweezers.Comment: 8 page

Fine-Grained Complexity of Analyzing Compressed Data: Quantifying Improvements over Decompress-And-Solve

Can we analyze data without decompressing it? As our data keeps growing, understanding the time complexity of problems on compressed inputs, rather than in convenient uncompressed forms, becomes more and more relevant. Suppose we are given a compression of size $n$ of data that originally has size $N$, and we want to solve a problem with time complexity $T(\cdot)$. The naive strategy of "decompress-and-solve" gives time $T(N)$, whereas "the gold standard" is time $T(n)$: to analyze the compression as efficiently as if the original data was small. We restrict our attention to data in the form of a string (text, files, genomes, etc.) and study the most ubiquitous tasks. While the challenge might seem to depend heavily on the specific compression scheme, most methods of practical relevance (Lempel-Ziv-family, dictionary methods, and others) can be unified under the elegant notion of Grammar Compressions. A vast literature, across many disciplines, established this as an influential notion for Algorithm design. We introduce a framework for proving (conditional) lower bounds in this field, allowing us to assess whether decompress-and-solve can be improved, and by how much. Our main results are: - The $O(nN\sqrt{\log{N/n}})$ bound for LCS and the $O(\min\{N \log N, nM\})$ bound for Pattern Matching with Wildcards are optimal up to $N^{o(1)}$ factors, under the Strong Exponential Time Hypothesis. (Here, $M$ denotes the uncompressed length of the compressed pattern.) - Decompress-and-solve is essentially optimal for Context-Free Grammar Parsing and RNA Folding, under the $k$-Clique conjecture. - We give an algorithm showing that decompress-and-solve is not optimal for Disjointness

Paradigms for computational nucleic acid design

The design of DNA and RNA sequences is critical for many endeavors, from DNA nanotechnology, to PCR‐based applications, to DNA hybridization arrays. Results in the literature rely on a wide variety of design criteria adapted to the particular requirements of each application. Using an extensively studied thermodynamic model, we perform a detailed study of several criteria for designing sequences intended to adopt a target secondary structure. We conclude that superior design methods should explicitly implement both a positive design paradigm (optimize affinity for the target structure) and a negative design paradigm (optimize specificity for the target structure). The commonly used approaches of sequence symmetry minimization and minimum free‐energy satisfaction primarily implement negative design and can be strengthened by introducing a positive design component. Surprisingly, our findings hold for a wide range of secondary structures and are robust to modest perturbation of the thermodynamic parameters used for evaluating sequence quality, suggesting the feasibility and ongoing utility of a unified approach to nucleic acid design as parameter sets are refined further. Finally, we observe that designing for thermodynamic stability does not determine folding kinetics, emphasizing the opportunity for extending design criteria to target kinetic features of the energy landscape