Conformational Search for the Protein Native State

2010 ◽  
pp. 431-452 ◽  
Author(s):  
Amarda Shehu
Keyword(s):  
Conformational Search ◽  
Native State

IN SEARCH OF THE PROTEIN NATIVE STATE WITH A PROBABILISTIC SAMPLING APPROACH

2011 ◽  
Vol 09 (03) ◽  
pp. 383-398 ◽  
Author(s):  
BRIAN OLSON ◽  
KEVIN MOLLOY ◽  
AMARDA SHEHU
Keyword(s):  
Structure Prediction ◽  
Computational Models ◽  
Three Dimensional ◽  
Structural Diversity ◽  
Search Space ◽  
Conformational Space ◽  
Conformational Search ◽  
Dimensional Structure ◽  
Computational Techniques ◽  
Native State

The three-dimensional structure of a protein is a key determinant of its biological function. Given the cost and time required to acquire this structure through experimental means, computational models are necessary to complement wet-lab efforts. Many computational techniques exist for navigating the high-dimensional protein conformational search space, which is explored for low-energy conformations that comprise a protein's native states. This work proposes two strategies to enhance the sampling of conformations near the native state. An enhanced fragment library with greater structural diversity is used to expand the search space in the context of fragment-based assembly. To manage the increased complexity of the search space, only a representative subset of the sampled conformations is retained to further guide the search towards the native state. Our results make the case that these two strategies greatly enhance the sampling of the conformational space near the native state. A detailed comparative analysis shows that our approach performs as well as state-of-the-art ab initio structure prediction protocols.

scholarly journals “Register-shift” insulin analogs uncover constraints of proteotoxicity in protein evolution

2020 ◽  
Vol 295 (10) ◽  
pp. 3080-3098 ◽  
Author(s):  
Nischay K. Rege ◽  
Ming Liu ◽  
Balamurugan Dhayalan ◽  
Yen-Shan Chen ◽  
Nicholas A. Smith ◽  
...  
Keyword(s):  
Self Assembly ◽  
Md Simulations ◽  
Binding Mode ◽  
Conformational Search ◽  
Evolutionary Constraint ◽  
Native State ◽  
Signaling Complex ◽  
Molecular Determinants ◽  
Register Shift

Globular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e. a conformational search that is both efficient and robustly minimizes misfolding. Studies of mutations associated with toxic misfolding have yielded insights into molecular determinants of protein foldability. Of particular interest are residues that are conserved yet dispensable in the native state. Here, we exploited the mutant proinsulin syndrome (a major cause of permanent neonatal-onset diabetes mellitus) to investigate whether toxic misfolding poses an evolutionary constraint. Our experiments focused on an invariant aromatic motif (PheB24–PheB25–TyrB26) with complementary roles in native self-assembly and receptor binding. A novel class of mutations provided evidence that insulin can bind to the insulin receptor (IR) in two different modes, distinguished by a “register shift” in this motif, as visualized by molecular dynamics (MD) simulations. Register-shift variants are active but defective in cellular foldability and exquisitely susceptible to fibrillation in vitro. Indeed, expression of the corresponding proinsulin variant induced endoplasmic reticulum stress, a general feature of the mutant proinsulin syndrome. Although not present among vertebrate insulin and insulin-like sequences, a prototypical variant ([GlyB24]insulin) was as potent as WT insulin in a rat model of diabetes. Although in MD simulations the shifted register of receptor engagement is compatible with the structure and allosteric reorganization of the IR-signaling complex, our results suggest that this binding mode is associated with toxic misfolding and so is disallowed in evolution. The implicit threat of proteotoxicity limits sequence variation among vertebrate insulins and insulin-like growth factors.

Existence of DNA in yeast microbodies

1978 ◽  
Vol 36 (2) ◽  
pp. 232-233
Author(s):  
Masako Osumi ◽  
Misuzu Nagano ◽  
Hiroko Kazama
Keyword(s):  
Catalase Activity ◽  
Buoyant Density ◽  
Model System ◽  
Contour Length ◽  
Native State ◽  
Normal Alkane ◽  
Remarkable Increase ◽  
Dna Molecule ◽  
Mitochondrial Dnas

We have found that microbodies appeared profusely together with a remarkable increase in catalase activity in normal alkane-grown cells of hydrocarbon-utilizing Candida yeasts, and that the microbodies multiplied by division in these cells. These features of Candida yeasts seem to provide a useful model system for studies on the biogenesis of the microbody. Subsequently, we have succeeded in isolation of Candida microbodies in an apparently native state, as judged biochemically and morphologically. The presence of DNA in the purified microbody fraction thus obtained was proved by the diphenylamine method. DNA molecule of about 15 urn in contour length was released from an isolated microbody. The physicochemical analyses of the microbody DNA revealed that its buoyant density differed from nuclear and mitochondrial DNAs. All these results lead us to the possibility that there is a novel type of DNA in microbodies.

Electron Microscopic Observation of Biological Specimens in Their Native State by Employing Cryogenic Techniques

1972 ◽  
Vol 30 ◽  
pp. 410-411 ◽  
Author(s):  
Tokio Nei ◽  
Haruo Yotsumoto ◽  
Yoichi Hasegawa ◽  
Yuji Nagasawa
Keyword(s):  
Electron Microscopic Observation ◽  
Surface Structures ◽  
Specimen Preparation ◽  
Native State ◽  
Electron Microscopic ◽  
Biological Specimen ◽  
Specimen Holder ◽  
Cold Stage ◽  
Preparation Techniques ◽  
Scanning Electron

In order to observe biological specimens in their native state, that is, still containing their water content, various methods of specimen preparation have been used, the principal two of which are the chamber method and the freeze method.Using its recently developed cold stage for installation in the pre-evacuation chamber of a scanning electron microscope, we have succeeded in directly observing a biological specimen in its frozen state without the need for such conventional specimen preparation techniques as drying and metallic vacuum evaporation. (Echlin, too, has reported on the observation of surface structures using the same freeze method.)In the experiment referred to herein, a small sliced specimen was place in the specimen holder. After it was rapidly frozen by freon cooled with liquid nitrogen, it was inserted into the cold stage of the specimen chamber.

Biodegradable Polyurethanes Cross-Linked by Multifunctional Compounds

2017 ◽  
Vol 14 (6) ◽  
pp. 778-784 ◽  
Author(s):  
Joanna Brzeska
Keyword(s):  
Polymer Structure ◽  
Cross Linking ◽  
Plant Oils ◽  
Lignocellulosic Materials ◽  
Soft Or ◽  
Native State ◽  
Synthetic Compounds ◽  
Multifunctional Compounds ◽  
Hard Segments ◽  
Synthetic Origin

Background: Cross-linking structure of polyurethanes determines no degradability of these materials. However, introducing the hydrolysable substrates (of natural or synthetic origin) into the cross-linked polyurethanes structure makes them biodegradable. Moreover compounds (such as polycaprolactone triol, glycerin, lysine triisocyanate, etc.) that are used for polyurethane cross-linking are degraded in non-toxic products. All these kinds of compounds can be introduced into soft or hard segments via urethane bonds. Objective: The review focuses on kind of multifunctional polyols and isocyanates, and low molecular crosslinkers used for cross-linked polyurethanes obtaining. These compounds are natural substrates (in the native state or after modification) or are synthetic compounds with degradable linkages. They belong to polyesters, plant oils, proteins, saccharides, and others (e.g. lignocellulosic materials), and they are synthesized chemically or via biosynthesis by algae, plants, microorganisms, and by animals. Conclusion: Incorporation of degradable groups (such as ester moieties) into the polymer structure, and using of substrates with the structure known and metabolized by microorganisms for soft or hard segments building, facilitate degradation of cross-linked polyurethanes.

scholarly journals Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”

2021 ◽  
Vol 22 (14) ◽  
pp. 7704
Author(s):  
Sayi’Mone Tati ◽  
Laleh Alisaraie
Keyword(s):  
Binding Affinity ◽  
Atp Hydrolysis ◽  
Critical Role ◽  
Motor Protein ◽  
Structural Data ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Conformational Search ◽  
Structural Mechanism

Dynein is a ~1.2 MDa cytoskeletal motor protein that carries organelles via retrograde transport in eukaryotic cells. The motor protein belongs to the ATPase family of proteins associated with diverse cellular activities and plays a critical role in transporting cargoes to the minus end of the microtubules. The motor domain of dynein possesses a hexameric head, where ATP hydrolysis occurs. The presented work analyzes the structure–activity relationship (SAR) of dynapyrazole A and B, as well as ciliobrevin A and D, in their various protonated states and their 46 analogues for their binding in the AAA1 subunit, the leading ATP hydrolytic site of the motor domain. This study exploits in silico methods to look at the analogues’ effects on the functionally essential subsites of the motor domain of dynein 1, since no similar experimental structural data are available. Ciliobrevin and its analogues bind to the ATP motifs of the AAA1, namely, the walker-A (W-A) or P-loop, the walker-B (W-B), and the sensor I and II. Ciliobrevin A shows a better binding affinity than its D analogue. Although the double bond in ciliobrevin A and D was expected to decrease the ligand potency, they show a better affinity to the AAA1 binding site than dynapyrazole A and B, lacking the bond. In addition, protonation of the nitrogen atom in ciliobrevin A and D, as well as dynapyrazole A and B, at the N9 site of ciliobrevin and the N7 of the latter increased their binding affinity. Exploring ciliobrevin A geometrical configuration suggests the E isomer has a superior binding profile over the Z due to binding at the critical ATP motifs. Utilizing the refined structure of the motor domain obtained through protein conformational search in this study exhibits that Arg1852 of the yeast cytoplasmic dynein could involve in the “glutamate switch” mechanism in cytoplasmic dynein 1 in lieu of the conserved Asn in AAA+ protein family.

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