A Modular Approach to Protein Design

1990 ◽  
Author(s):  
H. N. Bramson
Keyword(s):  
Protein Design ◽  
Modular Approach

scholarly journals Epistasis on the stability landscape of de novo TIM barrels explored by a modular design approach

2020 ◽  
Author(s):  
Sergio Romero-Romero ◽  
Miguel Costas ◽  
Daniel-Adriano Silva Manzano ◽  
Sina Kordes ◽  
Erendira Rojas-Ortega ◽  
...  
Keyword(s):  
Protein Stability ◽  
Protein Design ◽  
Modular Design ◽  
De Novo ◽  
Conformational Stability ◽  
Modular Approach ◽  
Structure And Stability ◽  
Custom Made ◽  
Tim Barrel ◽  
The Stability

AbstractThe design of stable proteins with custom-made functions is a major goal in biochemistry with practical relevance for our environment and society. High conformational stability lowers protein sensitivity to mutations and changes in the environment; thus, understanding and manipulating protein stability will expand the applications of de novo proteins. Since the (β/α)8-barrel or TIM-barrel fold is one of the most common functional scaffolds, in this work we designed a collection of stable de novo TIM barrels (NovoTIMs), using a computational fixed-backbone and modular approach based on improved hydrophobic packing of sTIM11, the first validated de novo TIM barrel. NovoTIMs navigate a region of the stability landscape previously uncharted by natural TIM barrels, with variations spanning 60 degrees in melting temperature and 25 kcal per mol in conformational stability throughout the designs. Significant non-additive or epistatic effects were observed when stabilizing mutations from different regions of the barrel were combined. The molecular basis of epistasis in NovoTIMs appears to be related to the extension of the hydrophobic cores. This study is an important step towards the fine-tuned modulation of protein stability by design.Significance StatementDe novo protein design expands our knowledge about protein structure and stability. The TIM barrel is a highly relevant fold used in nature to host a rich variety of catalytic functions. Here, we follow a modular approach to design and characterize a collection of de novo TIM barrels and subjected them to a thorough folding analysis. Non-additive effects modulate the increase in stability when different regions of the barrel are mutated, showing a wide variety of thermodynamic properties that allow them to navigate an unexplored region of the stability landscape found in natural TIM barrels. The design of stable proteins increases the applications of de novo proteins and provides more information on the molecular determinants that modulate structure and stability.

Protein-design papers challenged

Nature ◽  
2009 ◽  
Author(s):  
Erika Check Hayden
Keyword(s):  
Protein Design

A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

2019 ◽  
Author(s):  
Victor Bloemendal ◽  
Floris P. J. T. Rutjes ◽  
Thomas J. Boltje ◽  
Daan Sondag ◽  
Hidde Elferink ◽  
...  
Keyword(s):  
Biological Activity ◽  
Late Stage ◽  
Medicinal Chemistry ◽  
Cross Coupling ◽  
Modular Approach ◽  
Coupling Reactions ◽  
One Pot ◽  
Biologically Relevant ◽  
Cross Coupling Reactions ◽  
Chemistry Research

<p>In this manuscript we describe a modular pathway to synthesize biologically relevant (–)-<i>trans</i>-Δ<sup>8</sup>-THC derivatives, which can be used to modulate the pharmacologically important CB<sub>1</sub> and CB<sub>2</sub> receptors. This pathway involves a one-pot Friedel-Crafts alkylation/cyclization protocol, followed by Suzuki-Miyaura cross-coupling reactions and gives rise to a series of new Δ<sup>8</sup>-THC derivatives. In addition, we demonstrate using extensive NMR evidence that similar halide-substituted Friedel-Crafts alkylation/cyclization products in previous articles were wrongly assigned as the para-isomers, which also has consequence for the assignment of the subsequent cross-coupled products and interpretation of their biological activity. </p> <p>Considering the importance of the availability of THC derivatives in medicinal chemistry research and the fact that previously synthesized compounds were wrongly assigned, we feel this research is describing a straightforward pathway into new cannabinoids.</p>

The Total Synthesis of Rhabdastrellic Acid A

2018 ◽  
Author(s):  
Yaroslav Boyko ◽  
Christopher Huck ◽  
David Sarlah
Keyword(s):  
Total Synthesis ◽  
Late Stage ◽  
Cross Coupling ◽  
Side Chains ◽  
General Strategy ◽  
Modular Approach ◽  
Linear Sequence ◽  
Generating Sequence ◽  
First Time

<div>The first total synthesis of rhabdastrellic acid A, a highly cytotoxic isomalabaricane triterpenoid, has been accomplished in a linear sequence of 14 steps from commercial geranylacetone. The prominently strained <i>trans-syn-trans</i>-perhydrobenz[<i>e</i>]indene core characteristic of the isomalabaricanes is efficiently accessed in a selective manner for the first time through a rapid, complexity-generating sequence incorporating a reductive radical polyene cyclization, an unprecedented oxidative Rautenstrauch cycloisomerization, and umpolung 𝛼-substitution of a <i>p</i>-toluenesulfonylhydrazone with in situ reductive transposition. A late-stage cross-coupling in concert with a modular approach to polyunsaturated side chains renders this a general strategy for the synthesis of numerous family members of these synthetically challenging and hitherto inaccessible marine triterpenoids.</div>

The Staging of Large Wastewater Treatment Plants - A “Modular” Approach

1992 ◽  
Vol 25 (4-5) ◽  
pp. 67-73
Author(s):  
H. Fleckseder ◽  
L. Prendl ◽  
H. Meulenbroek
Keyword(s):  
Wastewater Treatment ◽  
Driving Force ◽  
Wastewater Treatment Plants ◽  
Aeration Tank ◽  
Modular Approach ◽  
Central European ◽  
Plant Hydraulics ◽  
The World ◽  
Whole Life Cycle ◽  
Over Time

The primary driving force for re-investments in wastewater treatment plants in Austria - and also other countries in Central Europe - is at present not an increase in load to treatment but a marked increase in effluent requirements to be fulfilled. (The re-investments necessary for sludge handling and treatment remain outside this paper.) Within a period of 20 years, the load specific requirements on aeration tank volume rose five- to tenfold, when Lv = 2.0 kg BOD5/(m3d) was the starting value, and roughly doubled for final clarifiers. In addition, the importance of the application and expansion of primary sedimentation decreased as well. This development over time in Central European countries as well as the need to utilize previous investments as long as possible - 35 to 60 years for civil works are common as periods of depreciation - indicate that investments in new plant at any location in the world have to consider the possible whole life cycle of a plant and that plant hydraulics becomes the “key hook” for expandability.

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