A robust class of stable proteins in the 2D HPC model

Abstract. The inverse protein folding problem is that of designing an amino acid sequence which has a prescribed native protein fold. This problem arises in drug design where a particular structure is necessary to ensure proper protein-protein interactions. The input to the inverse protein folding problem is a shape and the goal is to design a protein sequence with a unique native fold that closely approximates the input shape. Gupta et al. [1] introduced a design in the 2D HP model of Dill that can be used to approximate any given (2D) shape. They conjectured that the protein sequences of their design are stable but only proved the stability for an infinite class of very basic structures. In [2], we have introduced a refinement of the HP model, in which the cysteine and noncysteine hydrophobic monomers are distinguished and SS-bridges which two cysteines can form are taken into account in the energy function. This model was called the 2D HPC model. In [2], the snake structures in the HPC model were introduced and it was conjectured that they are stable. In this paper, we show that this conjecture is true for a subclass of snake structures. This subclass is robust enough to approximate any given 2D shape, although more coarsely than the general constructible structures proposed i

Exact, constraint-based structure prediction in simple protein models

Die Arbeit untersucht die exakte Vorhersage der Struktur von Proteinen in dreidimensionalen, abstrakten Proteinmodellen; insbesondere wird ein exakter Ansatz zur Strukturvorhersage in den HP-Modellen (Lau und Dill, ACS, 1989) des kubischen und kubisch-flächenzentrierten Gitters entwickelt und diskutiert. Im Gegensatz zu heuristischen Methoden liefert das vorgestellte exakte Verfahren beweisbar korrekte Strukturen. HP-Modelle (Hydrophob, Polar) repräsentieren die Rückgratkonformation eines Proteins durch Gitterpunkte und berücksichti\-gen ausschließlich die hydrophobe Wechselwirkung als treibende Kraft bei der Ausbildung der Proteinstruktur. Wesentlich für die erfolgreiche Umsetzung des vorgestellten Verfahrens ist die Verwendung von constraint-basierten Techniken. Im Zentrum steht die Berechnung und Anwendung hydrophober Kerne für die Strukturvorhersage

On a Generalized Levinthal's Paradox: The Role of Long- and Short Range Interactions in Complex Bio-molecular Reactions, Including Protein and DNA Folding

The current protein folding literature is reviewed. Two main approaches to the problem of folding were selected for this review: geometrical and biophysical. The geometrical approach allows the formulation of topological restrictions on folding, that are usually not taken into account in the construction of physical models. In particular, the topological constraints do not allow the known funnel-like energy landscape modeling, although most common methods of resolving the paradox are based on this method. The very paradox is based on the fact that complex molecules must reach their native conformations (complexes that result from reactions) in an exponentially long time, which clearly contradicts the observed experimental data. In this respect we considered the complexity of the reactions between ligands and proteins. On this general basis, the folding-reaction paradox was reformulated and generalized. We conclude that prospects for solving the paradox should be associated with incorporating a topology aspect in biophysical models of protein folding, through the construction of hybrid models. However, such models should explicitly include long-range force fields and local cell biological conditions, such as structured water complexes and photon/phonon/soliton waves, ordered in discrete frequency bands. In this framework, collective and coherent oscillations in, and between, macromolecules are instrumental in inducing intra- and intercellular resonance, serving as an integral guiding network of life communication: the electrome aspect of the cell. Yet, to identify the actual mechanisms underlying the bonds between molecules (atoms), it will be necessary to perform dedicated experiments to more definitely solve the particular time paradox. © 2017 Elsevier Ltd.The present results were partially obtained in the frame of state task of Ministry of Education and Science of Russia 1.4539.2017/8.9

Secondary structure-based template selection for fragment-assembly protein structure prediction

Proteins play critical biochemical roles in all living organisms; in human beings, they are the targets of 50% of all drugs. Although the first protein structure was determined 60 years ago, experimental techniques are still time and cost consuming. Consequently, in silico protein structure prediction, which is considered a main challenge in computational biology, is fundamental to decipher conformations of protein targets. This thesis contributes to the state of the art of fragment-assembly protein structure prediction. This category has been widely and thoroughly studied due to its application to any type of targets. While the majority of research focuses on enhancing the functions that are used to score fragments by incorporating new terms and optimising their weights, another important issue is how to pick appropriate fragments from a large pool of candidate structures. Since prediction of the main structural classes, i.e. mainly-alpha, mainly-beta and alpha-beta, has recently reached quite a high level of accuracy, we have introduced a novel approach by decreasing the size of the pool of candidate structures to comprise only proteins that share the same structural class a target is likely to adopt. Picking fragments from this customised set of known structures not only has contributed in generating decoys with higher level of accuracy but also has eliminated irrelevant parts of the search space which makes the selection of first models a less complicated process, addressing the inaccuracies of energy functions. In addition to the challenge of adopting a unique template structure for all targets, another one arises whenever relying on the same amount of corrections and fine tunings; such a phase may be damaging to “easy’ targets, i.e. those that comprise a relatively significant percentage of alpha helices. Owing to the sequence-structure correlation based on which fragment-based protein structure prediction was born, we have also proposed a customised phase of correction based on the structural class prediction of the target in question. After using secondary structure prediction as a “global feature” of a target, i.e. structural classes, we have also investigated its usage as a “local feature” to customise the number of candidate fragments, which is currently the same at all positions. Relying on the known facts regarding diversity of short fragments of helices, sheets and loops, the fragment insertion process has been adjusted to make “changes” relative to the expected complexity of each region. We have proved in this thesis the extent to which secondary structure features can be used implicitly or explicitly to enhance fragment assembly protein structure prediction

When to Hold and When to Fold: Studies on the topology of origami and linkages

Linkages and mechanisms are pervasive in physics and engineering as models for avariety of structures and systems, from jamming to biomechanics. With the increasein physical realizations of discrete shape-changing materials, such as metamaterials,programmable materials, and self-actuating structures, an increased understandingof mechanisms and how they can be designed is crucial. At a basic level, linkagesor mechanisms can be understood to be rigid bars connected at pivots around whichthey can rotate freely. We will have a particular focus on origami-like materials, anextension to linkages with the added constraint of faces. Self-actuated versions typ-ically start flat and when exposed to an external stimulus - such as a temperaturechange or magnetic field - spontaneously fold. Since these structures fold all at once,and the number of folding patterns accessible to a given origami are exponential, theyare prone to folding to a configuration other than the desired one. Other work hassuggested methods for avoiding this misfolding, but it assumes ideal, rigid origami. Here, we expand on these models to account for the elasticity of real structures andintroduce methods for accounting for Gaussian curvature in them. We also explorehow to find and set an upper bound on minimal forcing sets, or the minimum set offolds required to force an origami, and present a graph theory algorithm for findingthem in arbitrary origami. Taken altogether, these origami studies give insight intohow the physical properties of origami influence folding and a new set of tools foravoiding misfolding. Next, we turn back to a more fundamental study of linkagesand present a new method for finding the manifold of their critical points. We thendemonstrate a design protocol that utilizes this manifold to create linkages with tun-able motions, before turning to several example structures, including the four-barlinkage and the Kane-Lubensky chain

Studies on the Three-dimensional Structures of Proteins Using X-ray Crystallography

abstract: X-ray diffraction is the technique of choice to determine the three-dimensional structures of proteins. In this study it has been applied to solve the structure of the survival motor neuron (SMN) proteins, the Fenna-Mathews-Olson (FMO) from Pelodictyon phaeum (Pld. phaeum) protein, and the synthetic ATP binding protein DX. Spinal muscular atrophy (SMA) is an autosomal recessive genetic disease resulting in muscle atrophy and paralysis via degeneration of motor neurons in the spinal cord. In this work, we used X-ray diffraction technique to solve the structures of the three variant of the of SMN protein, namely SMN 1-4, SMN-WT, and SMN-Δ7. The SMN 1-4, SMN-WT, and SMN-Δ7 crystals were diffracted to 2.7 Å, 5.5 Å and 3.0 Å, respectively. The three-dimensional structures of the three SMN proteins have been solved. The FMO protein from Pld. phaeum is a water soluble protein that is embedded in the cytoplasmic membrane and serves as an energy transfer funnel between the chlorosome and the reaction center. The FMO crystal diffracted to 1.99Å resolution and the three-dimensional structure has been solved. In previous studies, double mutant, DX, protein was purified and crystallized in the presence of ATP (Simmons et al., 2010; Smith et al. 2007). DX is a synthetic ATP binding protein which resulting from a random selection of DNA library. In this study, DX protein was purified and crystallized without the presence of ATP to investigate the conformational change in DX structure. The crystals of DX were diffracted to 2.5 Å and the three-dimensional structure of DX has been solved.Dissertation/ThesisPh.D. Biochemistry 201