scholarly journals Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6963
Author(s):  
María Maciá ◽  
Raúl Porcar ◽  
Vicente Martí-Centelles ◽  
Eduardo García-Verdugo ◽  
Maria Isabel Burguete ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Conformational Changes ◽  
Experimental Work ◽  
Rational Design ◽  
Supramolecular Complex ◽  
Trial And Error ◽  
Mechanistic Studies ◽  
Complex Catalyst ◽  
Custom Design ◽  
Computational Calculations

Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process.

Hierarchy of π-Stacking Determines the Conformational Preference of Bis-Squaraines

2020 ◽  
Author(s):  
Abhishek Singh ◽  
Reman K. Singh ◽  
G Naresh Patwari
Keyword(s):  
Hydrogen Bonding ◽  
Rational Design ◽  
Biological Molecules ◽  
Conformational Space ◽  
X Ray Crystallography ◽  
Simple Strategy ◽  
Induced Folding ◽  
Π Stacking ◽  
Varying Length ◽  
Dynamics Simulations

The rational design of conformationally controlled foldable modules can lead to a deeper insight into the conformational space of complex biological molecules where non-covalent interactions such as hydrogen bonding and π-stacking are known to play a pivotal role. Squaramides are known to have excellent hydrogen bonding capabilities and hence, are ideal molecules for designing foldable modules that can mimic the secondary structures of bio-molecules. The π-stacking induced folding of bis-squaraines tethered using aliphatic primary and secondary-diamine linkers of varying length is explored with a simple strategy of invoking small perturbations involving the length linkers and degree of substitution. Solution phase NMR investigations in combination with molecular dynamics simulations suggest that bis-squaraines predominantly exist as extended conformations. Structures elucidated by X-ray crystallography confirmed a variety of folded and extended secondary conformations including hairpin turns and 𝛽-sheets which are determined by the hierarchy of π-stacking relative to N–H···O hydrogen bonds.

Hierarchy of π-Stacking Determines the Conformational Preference of Bis-Squaraines

2020 ◽  
Author(s):  
Abhishek Singh ◽  
Reman K. Singh ◽  
G Naresh Patwari
Keyword(s):  
Hydrogen Bonding ◽  
Rational Design ◽  
Biological Molecules ◽  
Conformational Space ◽  
X Ray Crystallography ◽  
Simple Strategy ◽  
Induced Folding ◽  
Π Stacking ◽  
Varying Length ◽  
Dynamics Simulations

The rational design of conformationally controlled foldable modules can lead to a deeper insight into the conformational space of complex biological molecules where non-covalent interactions such as hydrogen bonding and π-stacking are known to play a pivotal role. Squaramides are known to have excellent hydrogen bonding capabilities and hence, are ideal molecules for designing foldable modules that can mimic the secondary structures of bio-molecules. The π-stacking induced folding of bis-squaraines tethered using aliphatic primary and secondary-diamine linkers of varying length is explored with a simple strategy of invoking small perturbations involving the length linkers and degree of substitution. Solution phase NMR investigations in combination with molecular dynamics simulations suggest that bis-squaraines predominantly exist as extended conformations. Structures elucidated by X-ray crystallography confirmed a variety of folded and extended secondary conformations including hairpin turns and 𝛽-sheets which are determined by the hierarchy of π-stacking relative to N–H···O hydrogen bonds.

An Experiment in Problem Solving

1951 ◽  
Vol 3 (4) ◽  
pp. 184-197 ◽  
Author(s):  
J. W. Whitfield
Keyword(s):  
Problem Solving ◽  
Experimental Work ◽  
Human Subjects ◽  
Qualitative Difference ◽  
Trial And Error ◽  
Qualitative Nature ◽  
The Individual

Trial-and-error problems are described in terms of “stimulus” difficulty, which is a measure of the number of possible modes of response left to the individual when all the information given is taken into account; and “phenomenal” difficulty, which is a measure derived from the individual's performance. An experiment is described in which three types of problem were presented to human subjects. In all three problems the stimulus difficulty was calculable, stage by stage, in the solution. The problems differed in this stimulus difficulty and also in the qualitative nature of the information provided—from unequivocal to conditional. It is shown that the qualitative difference of the nature of the information bears most relationship to phenomenal difficulty. Some observations are made on the modes of solution adopted, and further experimental work is suggested.

scholarly journals Improving the Substrate Affinity and Catalytic Efficiency of β-Glucosidase Bgl3A from Talaromyces leycettanus JCM12802 by Rational Design

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1882
Author(s):  
Wei Xia ◽  
Yingguo Bai ◽  
Pengjun Shi
Keyword(s):  
Hydrogen Bonding ◽  
Rational Design ◽  
Substrate Binding ◽  
Enzymatic Saccharification ◽  
Catalytic Efficiency ◽  
Binding Pocket ◽  
Glycoside Hydrolases ◽  
Cellulosic Biomass ◽  
Substrate Affinity ◽  
Hydrogen Bonding Networks

Improving the substrate affinity and catalytic efficiency of β-glucosidase is necessary for better performance in the enzymatic saccharification of cellulosic biomass because of its ability to prevent cellobiose inhibition on cellulases. Bgl3A from Talaromyces leycettanus JCM12802, identified in our previous work, was considered a suitable candidate enzyme for efficient cellulose saccharification with higher catalytic efficiency on the natural substrate cellobiose compared with other β-glucosidase but showed insufficient substrate affinity. In this work, hydrophobic stacking interaction and hydrogen-bonding networks in the active center of Bgl3A were analyzed and rationally designed to strengthen substrate binding. Three vital residues, Met36, Phe66, and Glu168, which were supposed to influence substrate binding by stabilizing adjacent binding site, were chosen for mutagenesis. The results indicated that strengthening the hydrophobic interaction between stacking aromatic residue and the substrate, and stabilizing the hydrogen-bonding networks in the binding pocket could contribute to the stabilized substrate combination. Four dominant mutants, M36E, M36N, F66Y, and E168Q with significantly lower Km values and 1.4–2.3-fold catalytic efficiencies, were obtained. These findings may provide a valuable reference for the design of other β-glucosidases and even glycoside hydrolases.

scholarly journals A rational pre-catalyst design for bis-phosphine mono-oxide palladium catalyzed reactions

2017 ◽  
Vol 8 (4) ◽  
pp. 2841-2851 ◽  
Author(s):  
Yining Ji ◽  
Hongming Li ◽  
Alan M. Hyde ◽  
Qinghao Chen ◽  
Kevin M. Belyk ◽  
...  
Keyword(s):  
Rational Design ◽  
Catalyst Design ◽  
Mechanistic Studies ◽  
Catalyst Activation ◽  
Palladium Catalyzed ◽  
Catalyzed Reactions

Detailed mechanistic studies of a Pd-catalyzed asymmetric C–N coupling led to a rational design of a new series of bis-phosphine mono-oxides ligated Pd(ii) pre-catalysts that allow for reliable and complete catalyst activation.

Rational design of an influenza subunit vaccine powder with sugar glass technology: Preventing conformational changes of haemagglutinin during freezing and freeze-drying

Vaccine ◽  
2007 ◽  
Vol 25 (35) ◽  
pp. 6447-6457 ◽  
Author(s):  
J-P. Amorij ◽  
J. Meulenaar ◽  
W.L.J. Hinrichs ◽  
T. Stegmann ◽  
A. Huckriede ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Subunit Vaccine ◽  
Rational Design ◽  
Freeze Drying ◽  
Glass Technology ◽  
Sugar Glass

Hydrogen bonding interactions affect the hierarchical self-assembly and secondary structures of comb-like polypeptide supramolecular complexes displaying photoresponsive behavior

RSC Advances ◽  
2016 ◽  
Vol 6 (56) ◽  
pp. 51456-51469 ◽  
Author(s):  
Mohamed Gamal Mohamed ◽  
Jia-Huei Tu ◽  
Shih-Hung Huang ◽  
Yeo-Wan Chiang ◽  
Shiao-Wei Kuo
Keyword(s):  
Hydrogen Bonding ◽  
Long Range ◽  
Self Assembly ◽  
Secondary Structures ◽  
Supramolecular Complex ◽  
Supramolecular Complexes ◽  
Hydrogen Bonding Interactions ◽  
Lamellae Structure

Hierarchical lamellae-within-lamellae structure for the PTyr/AzoPy-C16 supramolecular complex, featuring long-range-ordered lamellae arising from the PTyr within lamellae arising from AzoPy-C16 units oriented in a perpendicular manner.

scholarly journals Cryo-electron Microscopy Structure and Transport Mechanism of a Wall Teichoic Acid ABC Transporter

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Li Chen ◽  
Wen-Tao Hou ◽  
Tao Fan ◽  
Banghui Liu ◽  
Ting Pan ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Rational Design ◽  
Teichoic Acid ◽  
Inhibitory Mechanism ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Design And Optimization ◽  
Cryo Electron Microscopy

ABSTRACT The wall teichoic acid (WTA) is a major cell wall component of Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), a common cause of fatal clinical infections in humans. Thus, the indispensable ABC transporter TarGH, which flips WTA from cytoplasm to extracellular space, becomes a promising target of anti-MRSA drugs. Here, we report the 3.9-Å cryo-electron microscopy (cryo-EM) structure of a 50% sequence-identical homolog of TarGH from Alicyclobacillus herbarius at an ATP-free and inward-facing conformation. Structural analysis combined with activity assays enables us to clearly decode the binding site and inhibitory mechanism of the anti-MRSA inhibitor Targocil, which targets TarGH. Moreover, we propose a “crankshaft conrod” mechanism utilized by TarGH, which can be applied to similar ABC transporters that translocate a rather big substrate through relatively subtle conformational changes. These findings provide a structural basis for the rational design and optimization of antibiotics against MRSA. IMPORTANCE The wall teichoic acid (WTA) is a major component of cell wall and a pathogenic factor in methicillin-resistant Staphylococcus aureus (MRSA). The ABC transporter TarGH is indispensable for flipping WTA precursor from cytoplasm to the extracellular space, thus making it a promising drug target for anti-MRSA agents. The 3.9-Å cryo-EM structure of a TarGH homolog helps us to decode the binding site and inhibitory mechanism of a recently reported inhibitor, Targocil, and provides a structural platform for rational design and optimization of potential antibiotics. Moreover, we propose a “crankshaft conrod” mechanism to explain how a big substrate is translocated through subtle conformational changes of type II exporters. These findings advance our understanding of anti-MRSA drug design and ABC transporters.

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