scholarly journals How the biotin–streptavidin interaction was made even stronger: investigation via crystallography and a chimaeric tetramer

2011 ◽  
Vol 435 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Claire E. Chivers ◽  
Apurba L. Koner ◽  
Edward D. Lowe ◽  
Mark Howarth
Keyword(s):  
Thermal Stability ◽  
Hydrogen Bond ◽  
Structural Features ◽  
Dissociation Pathway ◽  
Affinity Tags ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Biotin Binding ◽  
Non Covalent Interactions ◽  
Covalent Interactions

The interaction between SA (streptavidin) and biotin is one of the strongest non-covalent interactions in Nature. SA is a widely used tool and a paradigm for protein–ligand interactions. We previously developed a SA mutant, termed Tr (traptavidin), possessing a 10-fold lower off-rate for biotin, with increased mechanical and thermal stability. In the present study, we determined the crystal structures of apo-Tr and biotin–Tr at 1.5 Å resolution. In apo-SA the loop (L3/4), near biotin's valeryl tail, is typically disordered and open, but closes upon biotin binding. In contrast, L3/4 was shut in both apo-Tr and biotin–Tr. The reduced flexibility of L3/4 and decreased conformational change on biotin binding provide an explanation for Tr's reduced biotin off- and on-rates. L3/4 includes Ser45, which forms a hydrogen bond to biotin consistently in Tr, but erratically in SA. Reduced breakage of the biotin–Ser45 hydrogen bond in Tr is likely to inhibit the initiating event in biotin's dissociation pathway. We generated a Tr with a single biotin-binding site rather than four, which showed a simi-larly low off-rate, demonstrating that Tr's low off-rate was governed by intrasubunit effects. Understanding the structural features of this tenacious interaction may assist the design of even stronger affinity tags and inhibitors.

scholarly journals Molecular determinants and bottlenecks in the unbinding dynamics of biotin-streptavidin

2017 ◽  
Author(s):  
Pratyush Tiwary
Keyword(s):  
Atomistic Simulations ◽  
Enhanced Sampling ◽  
Protein Ligand Interactions ◽  
Direct Benefits ◽  
Molecular Determinants ◽  
Bond Stretching ◽  
Ligand Interactions ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Insight Into

Biotin-streptavidin is a very popular system used to gain insight into protein-ligand interactions. In its tetrameric form, it is well-known for its extremely long residence times, being one of the strongest known non-covalent interactions in nature, and is heavily used across the biotechnological industry. In this work we gain understanding into the molecular determinants and bottlenecks in the unbinding of the dimeric biotinstreptavidin system in its wild type and with N23A mutation. Using new enhanced sampling methods with full atomistic resolution, we reproduce the variation caused by N23A mutation in experimentally reported residence time. We also answer a longstanding question regarding cause/effect in the coupled events of bond stretching and bond hydration during unbinding and establish that in this system, it is the bond stretching and not hydration which forms the bottleneck in the early parts of the unbinding. We believe these calculations represent a step forward in the use of atomistic simulations to study pharmacodynamics. An improved understanding of biotin-streptavidin unbinding dynamics should also have direct benefits in biotechnological and nanobiotechnological applications.

scholarly journals New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

2016 ◽  
Vol 12 ◽  
pp. 2834-2848 ◽  
Author(s):  
Pavel Nagorny ◽  
Zhankui Sun
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Recent Progress ◽  
Halogen Bonds ◽  
Hydrogen Bond Donor ◽  
New Approaches ◽  
Substrate Activation ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Hydrogen Bond Donors

Hydrogen bond donor catalysis represents a rapidly growing subfield of organocatalysis. While traditional hydrogen bond donors containing N–H and O–H moieties have been effectively used for electrophile activation, activation based on other types of non-covalent interactions is less common. This mini review highlights recent progress in developing and exploring new organic catalysts for electrophile activation through the formation of C–H hydrogen bonds and C–X halogen bonds.

scholarly journals Chain stopper engineering for hydrogen bonded supramolecular polymers

2010 ◽  
Vol 6 ◽  
pp. 869-875 ◽  
Author(s):  
Thomas Pinault ◽  
Bruno Andrioletti ◽  
Laurent Bouteiller
Keyword(s):  
Hydrogen Bond ◽  
Molar Mass ◽  
Strong Hydrogen Bond ◽  
Supramolecular Polymers ◽  
Supramolecular Polymer ◽  
Hydrogen Bond Donor ◽  
Linear Chains ◽  
Non Covalent Interactions ◽  
Viscous Solutions ◽  
Covalent Interactions

Supramolecular polymers are linear chains of low molar mass monomers held together by reversible and directional non-covalent interactions, which can form gels or highly viscous solutions if the self-assembled chains are sufficiently long and rigid. The viscosity of these solutions can be controlled by adding monofunctional compounds, which interact with the chain extremities: chain stoppers. We have synthesized new substituted ureas and thioureas and tested them as chain stoppers for a bis-urea based supramolecular polymer. In particular, the bis-thiourea analogue of the bis-urea monomer is shown not to form a supramolecular polymer, but a good chain stopper, because it is a strong hydrogen bond donor and a weak acceptor. Moreover, all substituted ureas tested reduce the viscosity of the supramolecular polymer solutions, but the best chain stopper is obtained when two hydrogen bond acceptors are placed in the same relative position as for the monomer and when no hydrogen bond donor is present.

Supramolecular organization of phthalocyanines: from solution to surface

2009 ◽  
Vol 13 (04n05) ◽  
pp. 471-480 ◽  
Author(s):  
M. Victoria Martínez-Díaz ◽  
Giovanni Bottari
Keyword(s):  
Photophysical Properties ◽  
Building Blocks ◽  
Supramolecular Interactions ◽  
Supramolecular Organization ◽  
Supramolecular Systems ◽  
Ligand Interactions ◽  
Donor Acceptor ◽  
Interesting Class ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Phthalocyanines are an interesting class of aromatic macrocycles which possess exciting electrical, redox and photophysical properties that make them ideal building blocks for applications in different technological fields. However, the incorporation of phthalocyanines into devices is often tied to the possibility of organizing these macrocycles into arrays using supramolecular interactions. To date, several supramolecular motifs such as hydrogen-bonding, donor-acceptor or metal-ligand interactions have been used to promote the phthalocyanines' organization in solution. Furthermore, such weak, non-covalent interactions have also been widely employed to foster the organization of these macrocycles in condensed phases such as liquid-crystals or thin films. This micro-review provides a brief overview of the contribution made by some research groups in Spain towards the preparation of organized phthalocyanine-based supramolecular systems.

scholarly journals Rotational Spectroscopy Meets Quantum Chemistry for Analyzing Substituent Effects on Non-Covalent Interactions: The Case of the Trifluoroacetophenone-Water Complex

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4899
Author(s):  
Juncheng Lei ◽  
Silvia Alessandrini ◽  
Junhua Chen ◽  
Yang Zheng ◽  
Lorenzo Spada ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Substituent Effects ◽  
Equilibrium Structure ◽  
Proton Donor ◽  
Rotational Spectroscopy ◽  
Donor And Acceptor ◽  
Analogous Complex ◽  
Non Covalent Interactions ◽  
Covalent Interactions

The most stable isomer of the 1:1 complex formed by 2,2,2-trifluoroacetophenone and water has been characterized by combining rotational spectroscopy in supersonic expansion and state-of-the-art quantum-chemical computations. In the observed isomer, water plays the double role of proton donor and acceptor, thus forming a seven-membered ring with 2,2,2-trifluoroacetophenone. Accurate intermolecular parameters featuring one classical O-H···O hydrogen bond and one weak C-H···O hydrogen bond have been determined by means of a semi-experimental approach for equilibrium structure. Furthermore, insights on the nature of the established non-covalent interactions have been unveiled by means of different bond analyses. The comparison with the analogous complex formed by acetophenone with water points out the remarkable role played by fluorine atoms in tuning non-covalent interactions.

scholarly journals Graphlet signature-based scoring method to estimate protein–ligand binding affinity

2014 ◽  
Vol 1 (4) ◽  
pp. 140306 ◽  
Author(s):  
Omkar Singh ◽  
Kunal Sawariya ◽  
Polamarasetty Aparoy
Keyword(s):  
Hydrogen Bond ◽  
Ligand Binding ◽  
Interaction Networks ◽  
Scoring Method ◽  
Ligand Interaction ◽  
Ligand Affinity ◽  
Protein Ligand Interactions ◽  
Residue Interaction ◽  
Ligand Interactions ◽  
Cox 2

Over the years, various computational methodologies have been developed to understand and quantify receptor–ligand interactions. Protein–ligand interactions can also be explained in the form of a network and its properties. The ligand binding at the protein-active site is stabilized by formation of new interactions like hydrogen bond, hydrophobic and ionic. These non-covalent interactions when considered as links cause non-isomorphic sub-graphs in the residue interaction network. This study aims to investigate the relationship between these induced sub-graphs and ligand activity. Graphlet signature-based analysis of networks has been applied in various biological problems; the focus of this work is to analyse protein–ligand interactions in terms of neighbourhood connectivity and to develop a method in which the information from residue interaction networks, i.e. graphlet signatures, can be applied to quantify ligand affinity. A scoring method was developed, which depicts the variability in signatures adopted by different amino acids during inhibitor binding, and was termed as GSUS (graphlet signature uniqueness score). The score is specific for every individual inhibitor. Two well-known drug targets, COX-2 and CA-II and their inhibitors, were considered to assess the method. Residue interaction networks of COX-2 and CA-II with their respective inhibitors were used. Only hydrogen bond network was considered to calculate GSUS and quantify protein–ligand interaction in terms of graphlet signatures. The correlation of the GSUS with pIC 50 was consistent in both proteins and better in comparison to the Autodock results. The GSUS scoring method was better in activity prediction of molecules with similar structure and diverse activity and vice versa. This study can be a major platform in developing approaches that can be used alone or together with existing methods to predict ligand affinity from protein–ligand complexes.

scholarly journals Novel Protease Inhibitors (PIs) Containing Macrocyclic Components and 3(R),3a(S),6a(R)-bis-Tetrahydrofuranylurethane That Are Potent against Multi-PI-Resistant HIV-1 Variants In Vitro

2010 ◽  
Vol 54 (8) ◽  
pp. 3460-3470 ◽  
Author(s):  
Yasushi Tojo ◽  
Yasuhiro Koh ◽  
Masayuki Amano ◽  
Manabu Aoki ◽  
Debananda Das ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Molecular Design ◽  
Antiviral Agent ◽  
Structural Features ◽  
Biological Properties ◽  
Van Der Waals Interactions ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Hiv 1

ABSTRACT Natural products with macrocyclic structural features often display intriguing biological properties. Molecular design incorporating macrocycles may lead to molecules with unique protein-ligand interactions. We generated novel human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) containing a macrocycle and bis-tetrahydrofuranylurethane. Four such compounds exerted potent activity against HIV-1LAI and had 50% effective concentrations (EC50s) of as low as 0.002 μM with minimal cytotoxicity. GRL-216 and GRL-286 blocked the replication of HIV-1NL4-3 variants selected by up to 5 μM saquinavir, ritonavir, nelfinavir, lopinavir, or atazanavir; they had EC50s of 0.020 to 0.046 μM and potent activities against six multi-PI-resistant clinical HIV-1 (HIVmPIr ) variants with EC50s of 0.027 to 0.089 μM. GRL-216 and -286 also blocked HIV-1 protease dimerization as efficiently as darunavir. When HIV-1NL4-3 was selected by GRL-216, it replicated progressively more poorly and failed to replicate in the presence of >0.26 μM GRL-216, suggesting that the emergence of GRL-216-resistant HIV-1 variants is substantially delayed. At passage 50 with GRL-216 (the HIV isolate selected with GRL-216 at up to 0.16 μM [HIV216-0.16 μM]), HIV-1NL4-3 containing the L10I, L24I, M46L, V82I, and I84V mutations remained relatively sensitive to PIs, including darunavir, with the EC50s being 3- to 8-fold-greater than the EC50 of each drug for HIV-1NL4-3. Interestingly, HIV216-0.16 μM had 10-fold increased sensitivity to tipranavir. Analysis of the protein-ligand X-ray structures of GRL-216 revealed that the macrocycle occupied a greater volume of the binding cavity of protease and formed greater van der Waals interactions with V82 and I84 than darunavir. The present data warrant the further development of GRL-216 as a potential antiviral agent for treating individuals harboring wild-type and/or HIVmPIr .

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