scholarly journals Evolving Notch polyQ tracts reveal possible solenoid interference elements

2016 ◽  
Author(s):  
Albert J. Erives
Keyword(s):  
Regulatory Proteins ◽  
Triplet Repeats ◽  
Hydrogen Bond Donor ◽  
Replication Slippage ◽  
Regulatory Domains ◽  
Intrinsically Disordered ◽  
Notch Protein ◽  
Donor And Acceptor ◽  
Terminal Loop ◽  
Structural Principles

ABSTRACTPolyglutamine (polyQ) tracts in regulatory proteins are extremely polymorphic. As functional elements under selection for length, triplet repeats are prone to DNA replication slippage and indel mutations. Many polyQ tracts are also embedded within intrinsically disordered domains, which are less constrained, fast evolving, and difficult to characterize. To identify structural principles underlying polyQ tracts in disordered regulatory domains, here I analyze deep evolution of metazoan Notch polyQ tracts, which can generate alleles causing developmental and neurogenic defects. I show that Notch features polyQ tract turnover that is restricted to a discrete number of conserved “polyQ insertion slots”. Notch polyQ insertion slots are: (i) identifiable by an amphipathic “slot leader” motif; (ii) conserved as an intact C-terminal array in a 1-to-1 relationship with the N-terminal solenoid-forming ankyrin repeats (ARs); and (iii) enriched in carboxamide residues (Q/N), whose sidechains feature dual hydrogen bond donor and acceptor atoms. Correspondingly, the terminal loop and β-strand of each AR feature conserved carboxamide residues, which would be susceptible to folding interference by hydrogen bonding with residues outside the ARs. I thus suggest that Notch polyQ insertion slots constitute an array of AR interference elements (ARIEs). Notch ARIEs would dynamically compete with the delicate serial folding induced by adjacent ARs. Huntingtin, which harbors solenoid-forming HEAT repeats, also possesses a similar number of polyQ insertion slots. These results strongly suggest that intrinsically disordered interference arrays featuring carboxamide and polyQ enrichment are coupled proteodynamic modulators of solenoids.SIGNIFICANCENeurodegenerative disorders are often caused by expanded polyglutamine (polyQ) tracts embedded in the disordered regions of regulatory proteins, which are difficult to characterize structurally. To identify functional principles underlying polyQ tracts in disordered regulatory domains, I analyze evolution of the Notch protein, which can generate polyQ-related alleles causing neurodevelopmental defects. I show that Notch evolves polyQ tracts that come and go in a few conserved “polyQ insertion slots”. Several features suggest these slots are ankyrin repeat (AR) interference elements, which dynamically compete with the delicate solenoid formed by Notch. Huntingtin, whose polyQ expansions causes Huntington’s Disease in humans, also has solenoid-forming modules and polyQ insertion slots, suggesting a common architectural principle underlies solenoid-forming polyQ-rich proteins.

scholarly journals Machine learning models for hydrogen bond donor and acceptor strengths using large and diverse training data generated by first-principles interaction free energies

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Christoph A. Bauer ◽  
Gisbert Schneider ◽  
Andreas H. Göller
Keyword(s):  
Machine Learning ◽  
Hydrogen Bond ◽  
Hydrogen Bonding ◽  
Training Data ◽  
Free Energies ◽  
Hydrogen Bond Donor ◽  
Chemical Application ◽  
Hydrogen Bond Acceptor ◽  
Donor And Acceptor ◽  
Target Values

Abstract We present machine learning (ML) models for hydrogen bond acceptor (HBA) and hydrogen bond donor (HBD) strengths. Quantum chemical (QC) free energies in solution for 1:1 hydrogen-bonded complex formation to the reference molecules 4-fluorophenol and acetone serve as our target values. Our acceptor and donor databases are the largest on record with 4426 and 1036 data points, respectively. After scanning over radial atomic descriptors and ML methods, our final trained HBA and HBD ML models achieve RMSEs of 3.8 kJ mol−1 (acceptors), and 2.3 kJ mol−1 (donors) on experimental test sets, respectively. This performance is comparable with previous models that are trained on experimental hydrogen bonding free energies, indicating that molecular QC data can serve as substitute for experiment. The potential ramifications thereof could lead to a full replacement of wetlab chemistry for HBA/HBD strength determination by QC. As a possible chemical application of our ML models, we highlight our predicted HBA and HBD strengths as possible descriptors in two case studies on trends in intramolecular hydrogen bonding.

The hydrogen bond donor and acceptor ability of thioformic acid

2011 ◽  
Vol 22 (5) ◽  
pp. 1015-1030 ◽  
Author(s):  
Damanjit Kaur ◽  
Ritika Sharma ◽  
Darpandeep Aulakh
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bond Donor ◽  
Donor And Acceptor

Synthesis and preliminary bioactivity evaluation of new pregnane brassinosteroid-like compounds

2005 ◽  
Vol 83 (8) ◽  
pp. 1084-1092 ◽  
Author(s):  
Daniel G Rivera ◽  
Francisco Coll
Keyword(s):  
Hydrogen Bond ◽  
Plant Growth ◽  
Hypocotyl Elongation ◽  
Hydrogen Bond Donor ◽  
Donor And Acceptor ◽  
Plant Growth Promoting ◽  
Plant Growth Promoting Activity ◽  
Growth Promoting ◽  
Cotyledon Expansion

Seven new pregnane compounds bearing some representative A- and B-ring brassinosteroid functions, as well as hydrogen bond donor and acceptor ones on the D ring, were efficiently synthesized. The obtained compounds did not show remarkable plant growth-promoting activity in the radish hypocotyl elongation and cotyledon expansion bioassays, however, introducing oxygen and amino functions on the D ring led to an enhancement of the bioactivity. The 16β-functionalized pregnane brassinosteroid-like compounds were slightly more active than the 16α-functionalized ones.Key words: steroids, brassinosteroids, pregnane analogues.

scholarly journals Molecular Origin of Positive and Negative Electromechanical Response in Hydrogen-Bonded Systems

2019 ◽  
Author(s):  
Keith Werling ◽  
Daniel Lambrecht ◽  
Geoffrey Hutchison
Keyword(s):  
Applied Field ◽  
Electrostatic Interactions ◽  
Energy Surface ◽  
Piezoelectric Materials ◽  
Hydrogen Bond Donor ◽  
Hydrogen Bonding Interactions ◽  
Donor And Acceptor ◽  
Electronic Structure Methods ◽  
Hydrogen Bonded Systems ◽  
Hydrogen Bonded

Hydrogen bonds, ubiquitous in organic and biological materials, involve weak electrostatic interactions, which can geometrically distort in response to an applied electric field. This electromechanical response is a key component in a range of piezoelectric materials in applications including energy harvesting and sensing. In this work, we apply electronic structure methods across a combinatorial pool of over 218 hydrogen-bonded dimers to examine the connection between the electrostatics, potential energy surface, and the resulting electromechanical response. Strikingly, while inorganic piezomaterials typically exhibit positive piezo response, expanding in response to an applied field, we find that hydrogen bonding interactions instead typically exhibit negative response, contracting due to the local electrostatics between the hydrogen bond donor and acceptor functional groups.

scholarly journals Abundant α-Synuclein compact dimers

2019 ◽  
Author(s):  
Sofia Zaer ◽  
Paz Drori ◽  
Mario Lebendiker ◽  
Yair Razvag ◽  
Eitan Lerner
Keyword(s):  
Light Scattering ◽  
Single Molecule ◽  
Resonance Energy ◽  
Intrinsically Disordered Protein ◽  
Abundant Species ◽  
Anion Exchange Chromatography ◽  
Exchange Chromatography ◽  
Correlation Spectroscopy ◽  
Intrinsically Disordered ◽  
Donor And Acceptor

Abstractα-Synuclein (αSyn) is an intrinsically disordered protein that forms oligomers and fibrils associated with Parkinson’s disease. As such, the mechanism of its oligomerization and its possible links to neurotoxicity have been the focus of many studies. Out of the numerous oligomer types, dimers are the smallest oligomers of aSyn that have been reported. As such, αSyn dimers serve as the earliest steps in the nucleation of αSyn oligomers and later fibrils. Therefore, it is important to characterize αSyn dimers. The identification of αSyn dimers in ensemble-averaged measurements without the use of chemical modifications have been difficult, due to their apparent low abundance. Using analytical anion exchange chromatography coupled to multi angle light scattering as well as to dynamic light scattering, we show that recombinant αSyn is in equilibrium between different types of monomers and compact dimers, and that both are abundant. Additionally, bulk Förster resonance energy transfer (FRET), fluorescence cross-correlation spectroscopy (FCCS) of FRET and pulsed-interleaved excitation single-molecule FRET (PIE smFRET) measurements of mixtures of donor- and acceptor-labeled αSyn. These measurements indicated a dimer dissociation constant of 1.75 μM. We concluded that αSyn dimers exist as abundant species in equilibrium with monomers only if produced to reach concentrations of hundreds of nanomolar or above.

scholarly journals Synthon robustness by C-F groups in halogen substituted N-benzylideneanilines

2014 ◽  
Vol 70 (a1) ◽  
pp. C1811-C1811
Author(s):  
Gurpreet Kaur ◽  
Angshuman Roy Choudhury
Keyword(s):  
Crystal Structure ◽  
Crystal Engineering ◽  
Crystal Packing ◽  
Weak Interactions ◽  
Topological Analysis ◽  
Strong Hydrogen Bond ◽  
Hydrogen Bond Donor ◽  
Donor And Acceptor ◽  
The Impact ◽  
Organic Fluorine

The arrangement of the molecules in their crystal structure is controlled by the non-covalent intermolecular interactions other than the effectual space filling. The role of strong hydrogen bonds in guiding the crystal packing is well-known in the literature. But, how significant are the weak interactions in the field of crystal engineering, has yet not been fully understood. Our aim is to comprehend the nature and strength of the weak interactions involving fluorine in guiding the packing of small organic molecules in their respective crystal structure. The reason being the controversies, which are involved regarding the interactions offered by "organic fluorine"[1] and also due to the importance of these interactions in the pharmaceutical industry. Some of the research groups indicate the incapability of interactions offered by fluorine in the formation of supramolecular motifs, whereas other groups have indicated that substantial role is being played by fluorine in constructing the lattice through C-H···F, C-F···F and C-F···π interactions in the presence and absence of strong hydrogen bond donor and acceptor groups. To understand more about these interactions, we have chosen a model system of halogen substituted N-benzylideneanilines[2]. In this system, we have analysed the impact of fluorine mediated interactions on the crystal packing by having fluorine as a substituent on both the phenyl rings. Then the robustness of the synthons offered by organic fluorine has been anticipated in the same system, but with one of the substituent as chlorine or bromine in either of the phenyl ring. It has been observed that the replacement of the non-interacting fluorine by its heavier analogue has not altered the supramolecular motif, which was formed by the other fluorine. But the crystal packing has been found to be completely altered in the molecules where the interacting fluorine was replaced by its heavier analogue. Salient features of our computational studies, which include the calculation of the stabilization energies of the studied dimers using MP2 method and their topological analysis using AIM2000, to support the experimental observations will also be presented to highlight the sturdiness of the synthons formed by so called "organic fluorine".

C–H⋯S interaction exhibits all the characteristics of conventional hydrogen bonds

2020 ◽  
Vol 22 (31) ◽  
pp. 17482-17493 ◽  
Author(s):  
Sanat Ghosh ◽  
Pragya Chopra ◽  
Sanjay Wategaonkar
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Hydrogen Bond Donor ◽  
Donor And Acceptor

This is a tale of a pair of a hydrogen bond donor and acceptor, namely the CH donor and sulphur acceptor, neither of which is a conventional hydrogen bond participant.

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