Saturation and periodic self-stress in geometric auxetics.

The auxetic structures considered in this paper are three-dimensional periodic bar-and-joint frameworks. We start with the specific purpose of obtaining an auxetic design with underlying periodic graph of low valency. Adapting a general methodology, we produce an initial framework with valency seven and one degree of freedom. Then, we describe a saturation process, whereby edge orbits are added up to valency 16, with no alteration of the deformation path. This is reflected in a large dimension for the space of periodic self-stresses. The saturated version has higher crystallographic symmetry and allows a precise description of the deformation trajectory. Reducing saturation by adequate removal of edge orbits results in vast numbers of distinct auxetic designs which obey the same kinematics.

Periodic Auxetics: Structure and Design.

Materials science has adopted the term of auxetic behavior for structural deformations where stretching in some direction entails lateral widening, rather than lateral shrinking. Most studies, in the last three decades, have explored repetitive or cellular structures and used the notion of negative Poisson's ratio as the hallmark of auxetic behavior. However, no general auxetic principle has been established from this perspective. In the present article, we show that a purely geometric approach to periodic auxetics is apt to identify essential characteristics of frameworks with auxetic deformations and can generate a systematic and endless series of periodic auxetic designs. The critical features refer to convexity properties expressed through families of homothetic ellipsoids.

Auxetic deformations and elliptic curves.

In materials science and engineering, auxetic behavior refers to deformations of flexible structures where stretching in some direction involves lateral widening, rather than lateral shrinking. We address the problem of detecting auxetic behavior for flexible periodic bar-and-joint frameworks. Currently, the only known algorithmic solution is based on the rather heavy machinery of fixed-dimension semi-definite programming. In this paper we present a new, simpler algorithmic approach which is applicable to a natural family of three-dimensional periodic bar-and-joint frameworks with three degrees of freedom. This class includes most zeolite structures, which are important for applications in computational materials science. We show that the existence of auxetic deformations is related to properties of an associated elliptic curve. A fast algorithm for recognizing auxetic capabilities is obtained via the classical Aronhold invariants of the cubic form defining the curve. A related alternative is also considered.

New principles for auxetic periodic design.

We show that, for any given dimension d ≥ 2, the range of distinct possible designs for periodic frameworks with auxetic capabilities is infinite. We rely on a purely geometric approach to auxetic trajectories developed within our general theory of deformations of periodic frameworks.

Matching Multiple Rigid Domain Decompositions of Proteins.

We describe efficient methods for consistently coloring and visualizing collections of rigid cluster decompositions obtained from variations of a protein structure, and lay the foundation for more complex setups, that may involve different computational and experimental methods. The focus here is on three biological applications: the conceptually simpler problems of visualizing results of dilution and mutation analyses, and the more complex task of matching decompositions of multiple Nucleic Magnetic Resonance (NMR) models of the same protein. Implemented into the KINematics And RIgidity (KINARI) web server application, the improved visualization techniques give useful information about protein folding cores, help examining the effect of mutations on protein flexibility and function, and provide insights into the structural motions of Protein Data Bank proteins solved with solution NMR. These tools have been developed with the goal of improving and validating rigidity analysis as a credible coarse-grained model capturing essential information about a protein's slow motions near the native state.

Large scale rigidity-based flexibility analysis of biomolecules.

KINematics And RIgidity (KINARI) is an on-going project for in silico flexibility analysis of proteins. The new version of the software, Kinari-2, extends the functionality of our free web server KinariWeb, incorporates advanced web technologies, emphasizes the reproducibility of its experiments, and makes substantially improved tools available to the user. It is designed specifically for large scale experiments, in particular, for (a) very large molecules, including bioassemblies with high degree of symmetry such as viruses and crystals, (b) large collections of related biomolecules, such as those obtained through simulated dilutions, mutations, or conformational changes from various types of dynamics simulations, and (c) is intended to work as seemlessly as possible on the large, idiosyncratic, publicly available repository of biomolecules, the Protein Data Bank. We describe the system design, along with the main data processing, computational, mathematical, and validation challenges underlying this phase of the KINARI project.

Geometric auxetics.

We formulate a mathematical theory of auxetic behaviour based on one-parameter deformations of periodic frameworks. Our approach is purely geome- tric, relies on the evolution of the periodicity lattice and works in any dimension. We demonstrate its usefulness by predicting or recognizing, without experiment, computer simulations or numerical approximations, the auxetic capabilities of several well-known structures available in the literature. We propose new principles of auxetic design and rely on the stronger notion of expansive behaviour to provide an infinite supply of planar auxetic mechanisms and several new three-dimensional structures.

Liftings and stresses for planar periodic frameworks.

We formulate and prove a periodic analog of Maxwell's theorem relating stressed planar frameworks and their liftings to polyhedral surfaces with spherical topology. We use our lifting theorem to prove deformation and rigidity-theoretic properties for planar periodic pseudo-triangulations, generalizing features known for their finite counterparts. These properties are then applied to questions originating in mathematical crystallography and materials science, concerning planar periodic auxetic structures and ultrarigid periodic frameworks.

Frameworks with crystallographic symmetry.

Periodic frameworks with crystallographic symmetry are investigated from the perspective of a general deformation theory of periodic bar-and-joint structures in Euclidean spaces of arbitrary dimension. It is shown that natural parametrizations provide affine section descriptions for families of frameworks with a specified graph and symmetry. A simple geometrical setting for displacive phase transitions is obtained. Upper bounds are derived for the number of realizations of minimally rigid periodic graphs.

Rigidity analysis of protein biological assemblies and periodic crystal structures.

BACKGROUND: We initiate in silico rigidity-theoretical studies of biological assemblies and small crystals for protein structures. The goal is to determine if, and how, the interactions among neighboring cells and subchains affect the flexibility of a molecule in its crystallized state. We use experimental X-ray crystallography data from the Protein Data Bank (PDB). The analysis relies on an effcient graph-based algorithm. Computational experiments were performed using new protein rigidity analysis tools available in the new release of our KINARI-Web server http://kinari.cs.umass.edu. RESULTS: We provide two types of results: on biological assemblies and on crystals. We found that when only isolated subchains are considered, structural and functional information may be missed. Indeed, the rigidity of biological assemblies is sometimes dependent on the count and placement of hydrogen bonds and other interactions among the individual subchains of the biological unit. Similarly, the rigidity of small crystals may be affected by the interactions between atoms belonging to different unit cells. CONCLUSION: The rigidity analysis of a single asymmetric unit may not accurately reflect the protein's behavior in the tightly packed crystal environment. Using our KINARI software, we demonstrated that additional functional and rigidity information can be gained by analyzing a protein's biological assembly and/or crystal structure. However, performing a larger scale study would be computationally expensive (due to the size of the molecules involved). Overcoming this limitation will require novel mathematical and computational extensions to our software.

Towards accurate modeling of noncovalent interactions for protein rigidity analysis.

BACKGROUND: Protein rigidity analysis is an efficient computational method for extracting flexibility information from static, X-ray crystallography protein data. Atoms and bonds are modeled as a mechanical structure and analyzed with a fast graph-based algorithm, producing a decomposition of the flexible molecule into interconnected rigid clusters. The result depends critically on noncovalent atomic interactions, primarily on how hydrogen bonds and hydrophobic interactions are computed and modeled. Ongoing research points to the stringent need for benchmarking rigidity analysis software systems, towards the goal of increasing their accuracy and validating their results, either against each other and against biologically relevant (functional) parameters. We propose two new methods for modeling hydrogen bonds and hydrophobic interactions that more accurately reflect a mechanical model, without being computationally more intensive. We evaluate them using a novel scoring method, based on the B-cubed score from the information retrieval literature, which measures how well two cluster decompositions match. RESULTS: To evaluate the modeling accuracy of KINARI, our pebble-game rigidity analysis system, we use a benchmark data set of 20 proteins, each with multiple distinct conformations deposited in the Protein Data Bank. Cluster decompositions for them were previously determined with the RigidFinder method from Gerstein's lab and validated against experimental data. When KINARI's default tuning parameters are used, an improvement of the B-cubed score over a crude baseline is observed in 30% of this data. With our new modeling options, improvements were observed in over 70% of the proteins in this data set. We investigate the sensitivity of the cluster decomposition score with case studies on pyruvate phosphate dikinase and calmodulin. CONCLUSION: To substantially improve the accuracy of protein rigidity analysis systems, thorough benchmarking must be performed on all current systems and future extensions. We have measured the gain in performance by comparing different modeling methods for noncovalent interactions. We showed that new criteria for modeling hydrogen bonds and hydrophobic interactions can significantly improve the results. The two new methods proposed here have been implemented and made publicly available in the current version of KINARI (v1.3), together with the benchmarking tools, which can be downloaded from our software's website, http://kinari.cs.umass.edu.

Using rigidity analysis to probe mutation-induced structural changes in proteins.

Predicting the effect of a single amino acid substitution on the stability of a protein structure is a fundamental task in macromolecular modeling. It has relevance to drug design and understanding of disease-causing protein variants. We present KINARI-Mutagen, a web server for performing in silico mutation experiments on protein structures from the Protein Data Bank. Our rigidity-theoretical approach permits fast evaluation of the effects of mutations that may not be easy to perform in vitro, because it is not always possible to express a protein with a specific amino acid substitution. We use KINARI-Mutagen to identify critical residues, and we show that our predictions correlate with destabilizing mutations to glycine. In two in-depth case studies we show that the mutated residues identified by KINARI-Mutagen as critical correlate with experimental data, and would not have been identified by other methods such as Solvent Accessible Surface Area measurements or residue ranking by contributions to stabilizing interactions. We also generate 48 mutants for 14 proteins, and compare our rigidity-based results against experimental mutation stability data. KINARI-Mutagen is available at http://kinari.cs.umass.edu.

KINARI-Web: a server for protein rigidity analysis.

KINARI-Web is an interactive web server for performing rigidity analysis and visually exploring rigidity properties of proteins. It also provides tools for pre-processing the input data, such as selecting relevant chains from PDB files, adding hydrogen atoms and identifying stabilizing interactions. KINARI-Web offers a quick-start option for beginners, and highly customizable features for the experienced user. Chains, residues or atoms, as well as stabilizing constraints can be selected, removed or added, and the user can designate how different chemical interactions should be modeled during rigidity analysis. The enhanced Jmol-based visualizer allows for zooming in, highlighting or investigating different calculated rigidity properties of a molecular structure. KINARI-Web is freely available at http://kinari.cs.umass.edu.

A methodology for efficiently sampling the conformation space of molecular structures.

Motivated by recently developed computational techniques for studying protein flexibility, and their potential applications in docking, we propose an efficient method for sampling the conformational space of complex molecular structures. We focus on the loop closure problem, identified in the work of Thorpe and Lei (2004 Phil. Mag. 84 1323-31) as a primary bottleneck in the fast simulation of molecular motions. By modeling a molecular structure as a branching robot, we use an intuitive method in which the robot holds onto itself for maintaining loop constraints. New conformations are generated by applying random external forces, while internal, attractive forces pull the loops closed. Our implementation, tested on several model molecules with low number of degrees of freedom but many interconnected loops, gives promising results that show an almost four times speed-up on the benchmark cube-molecule of Thorpe and Lei.