Fast Frechet Distance Between Curves With Long Edges

Computing the Fr\'echet distance between two polygonal curves takes roughly quadratic time. In this paper, we show that for a special class of curves the Fr\'echet distance computations become easier. Let $P$ and $Q$ be two polygonal curves in $\mathbb{R}^d$ with $n$ and $m$ vertices, respectively. We prove four results for the case when all edges of both curves are long compared to the Fr\'echet distance between them: (1) a linear-time algorithm for deciding the Fr\'echet distance between two curves, (2) an algorithm that computes the Fr\'echet distance in $O((n+m)\log (n+m))$ time, (3) a linear-time $\sqrt{d}$-approximation algorithm, and (4) a data structure that supports $O(m\log^2 n)$-time decision queries, where $m$ is the number of vertices of the query curve and $n$ the number of vertices of the preprocessed curve

Path Similarity Analysis: A Method for Quantifying Macromolecular Pathways

abstract: Diverse classes of proteins function through large-scale conformational changes and various sophisticated computational algorithms have been proposed to enhance sampling of these macromolecular transition paths. Because such paths are curves in a high-dimensional space, it has been difficult to quantitatively compare multiple paths, a necessary prerequisite to, for instance, assess the quality of different algorithms. We introduce a method named Path Similarity Analysis (PSA) that enables us to quantify the similarity between two arbitrary paths and extract the atomic-scale determinants responsible for their differences. PSA utilizes the full information available in 3N-dimensional configuration space trajectories by employing the Hausdorff or Fréchet metrics (adopted from computational geometry) to quantify the degree of similarity between piecewise-linear curves. It thus completely avoids relying on projections into low dimensional spaces, as used in traditional approaches. To elucidate the principles of PSA, we quantified the effect of path roughness induced by thermal fluctuations using a toy model system. Using, as an example, the closed-to-open transitions of the enzyme adenylate kinase (AdK) in its substrate-free form, we compared a range of protein transition path-generating algorithms. Molecular dynamics-based dynamic importance sampling (DIMS) MD and targeted MD (TMD) and the purely geometric FRODA (Framework Rigidity Optimized Dynamics Algorithm) were tested along with seven other methods publicly available on servers, including several based on the popular elastic network model (ENM). PSA with clustering revealed that paths produced by a given method are more similar to each other than to those from another method and, for instance, that the ENM-based methods produced relatively similar paths. PSA applied to ensembles of DIMS MD and FRODA trajectories of the conformational transition of diphtheria toxin, a particularly challenging example, showed that the geometry-based FRODA occasionally sampled the pathway space of force field-based DIMS MD. For the AdK transition, the new concept of a Hausdorff-pair map enabled us to extract the molecular structural determinants responsible for differences in pathways, namely a set of conserved salt bridges whose charge-charge interactions are fully modelled in DIMS MD but not in FRODA. PSA has the potential to enhance our understanding of transition path sampling methods, validate them, and to provide a new approach to analyzing conformational transitions.The article is published at http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.100456

Computational Approaches to Simulation and Analysis of Large Conformational Transitions in Proteins

abstract: In a typical living cell, millions to billions of proteins—nanomachines that fluctuate and cycle among many conformational states—convert available free energy into mechanochemical work. A fundamental goal of biophysics is to ascertain how 3D protein structures encode specific functions, such as catalyzing chemical reactions or transporting nutrients into a cell. Protein dynamics span femtosecond timescales (i.e., covalent bond oscillations) to large conformational transition timescales in, and beyond, the millisecond regime (e.g., glucose transport across a phospholipid bilayer). Actual transition events are fast but rare, occurring orders of magnitude faster than typical metastable equilibrium waiting times. Equilibrium molecular dynamics (EqMD) can capture atomistic detail and solute-solvent interactions, but even microseconds of sampling attainable nowadays still falls orders of magnitude short of transition timescales, especially for large systems, rendering observations of such "rare events" difficult or effectively impossible. Advanced path-sampling methods exploit reduced physical models or biasing to produce plausible transitions while balancing accuracy and efficiency, but quantifying their accuracy relative to other numerical and experimental data has been challenging. Indeed, new horizons in elucidating protein function necessitate that present methodologies be revised to more seamlessly and quantitatively integrate a spectrum of methods, both numerical and experimental. In this dissertation, experimental and computational methods are put into perspective using the enzyme adenylate kinase (AdK) as an illustrative example. We introduce Path Similarity Analysis (PSA)—an integrative computational framework developed to quantify transition path similarity. PSA not only reliably distinguished AdK transitions by the originating method, but also traced pathway differences between two methods back to charge-charge interactions (neglected by the stereochemical model, but not the all-atom force field) in several conserved salt bridges. Cryo-electron microscopy maps of the transporter Bor1p are directly incorporated into EqMD simulations using MD flexible fitting to produce viable structural models and infer a plausible transport mechanism. Conforming to the theme of integration, a short compendium of an exploratory project—developing a hybrid atomistic-continuum method—is presented, including initial results and a novel fluctuating hydrodynamics model and corresponding numerical code.Dissertation/ThesisDoctoral Dissertation Physics 201

On the General Chain Pair Simplification Problem

The Chain Pair Simplification problem (CPS) was posed by Bereg et al. who were motivated by the problem of efficiently computing and visualizing the structural resemblance between a pair of protein backbones. In this problem, given two polygonal chains of lengths n and m, the goal is to simplify both of them simultaneously, so that the lengths of the resulting simplifications as well as the discrete Frechet distance between them are bounded. When the vertices of the simplifications are arbitrary (i.e., not necessarily from the original chains), the problem is called General CPS (GCPS). In this paper we consider for the first time the complexity of GCPS under both the discrete Frechet distance (GCPS-3F) and the Hausdorff distance (GCPS-2H). (In the former version, the quality of the two simplifications is measured by the discrete Fr\u27echet distance, and in the latter version it is measured by the Hausdorff distance.) We prove that GCPS-3F is polynomially solvable, by presenting an widetilde-O((n+m)^6 min{n,m}) time algorithm for the corresponding minimization problem. We also present an O((n+m)^4) 2-approximation algorithm for the problem. On the other hand, we show that GCPS-2H is NP-complete, and present an approximation algorithm for the problem