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 Controlling Exchange Pathways in Dynamic Supramolecular Polymers by Controlling Defects

2021 ◽  
Author(s):  
Anna Lucia de Marco ◽  
Davide Bochicchio ◽  
Andrea Gardin ◽  
Giovanni Doni ◽  
Giovanni M. Pavan
Keyword(s):  
Machine Learning ◽  
Coarse Grained ◽  
Supramolecular Polymers ◽  
Enhanced Sampling ◽  
Key Factors ◽  
Molecular Approaches ◽  
Molecular Determinants ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Intrinsic Dynamic

Supramolecular fibers, composed of monomers that self-assemble directionally <i>via</i> non-covalent interactions, are ubiquitous in nature and of great interest in chemistry. In these structures, the constitutive monomers continuously exchange in-and-out the assembly according to a well-defined supramolecular equilibrium. However, unraveling the exchange pathways and their molecular determinants constitutes a non-trivial challenge. Here we combine coarse-grained modeling, enhanced sampling, and machine learning to investigate the key factors controlling the monomer exchange pathways in synthetic supramolecular polymers having an intrinsic dynamic behavior. We demonstrate how the competition of directional <i>vs. </i>non-directional interactions between the monomers controls the creation/annihilation of defects in the supramolecular polymers, from where monomers exchange proceeds. This competition determines the exchange pathway, dictating whether a fiber statistically swaps monomers from the tips or all along its length. Finally, thanks to their generality, our models allow the investigation of molecular approaches to control the exchange pathways in these dynamic assemblies.<br>

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 Controlling Exchange Pathways in Dynamic Supramolecular Polymers by Controlling Defects

2021 ◽  
Author(s):  
Anna Lucia de Marco ◽  
Davide Bochicchio ◽  
Andrea Gardin ◽  
Giovanni Doni ◽  
Giovanni M. Pavan
Keyword(s):  
Machine Learning ◽  
Coarse Grained ◽  
Supramolecular Polymers ◽  
Enhanced Sampling ◽  
Key Factors ◽  
Molecular Approaches ◽  
Molecular Determinants ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Intrinsic Dynamic

Supramolecular fibers, composed of monomers that self-assemble directionally <i>via</i> non-covalent interactions, are ubiquitous in nature and of great interest in chemistry. In these structures, the constitutive monomers continuously exchange in-and-out the assembly according to a well-defined supramolecular equilibrium. However, unraveling the exchange pathways and their molecular determinants constitutes a non-trivial challenge. Here we combine coarse-grained modeling, enhanced sampling, and machine learning to investigate the key factors controlling the monomer exchange pathways in synthetic supramolecular polymers having an intrinsic dynamic behavior. We demonstrate how the competition of directional <i>vs. </i>non-directional interactions between the monomers controls the creation/annihilation of defects in the supramolecular polymers, from where monomers exchange proceeds. This competition determines the exchange pathway, dictating whether a fiber statistically swaps monomers from the tips or all along its length. Finally, thanks to their generality, our models allow the investigation of molecular approaches to control the exchange pathways in these dynamic assemblies.<br>

scholarly journals Controlling Exchange Pathways in Dynamic Supramolecular Polymers by Controlling Defects

2021 ◽  
Author(s):  
Anna Lucia de Marco ◽  
Davide Bochicchio ◽  
Andrea Gardin ◽  
Giovanni Doni ◽  
Giovanni M. Pavan
Keyword(s):  
Machine Learning ◽  
Coarse Grained ◽  
Supramolecular Polymers ◽  
Enhanced Sampling ◽  
Key Factors ◽  
Molecular Approaches ◽  
Molecular Determinants ◽  
Non Covalent Interactions ◽  
Covalent Interactions ◽  
Intrinsic Dynamic

Supramolecular fibers, composed of monomers that self-assemble directionally <i>via</i> non-covalent interactions, are ubiquitous in nature and of great interest in chemistry. In these structures, the constitutive monomers continuously exchange in-and-out the assembly according to a well-defined supramolecular equilibrium. However, unraveling the exchange pathways and their molecular determinants constitutes a non-trivial challenge. Here we combine coarse-grained modeling, enhanced sampling, and machine learning to investigate the key factors controlling the monomer exchange pathways in synthetic supramolecular polymers having an intrinsic dynamic behavior. We demonstrate how the competition of directional <i>vs. </i>non-directional interactions between the monomers controls the creation/annihilation of defects in the supramolecular polymers, from where monomers exchange proceeds. This competition determines the exchange pathway, dictating whether a fiber statistically swaps monomers from the tips or all along its length. Finally, thanks to their generality, our models allow the investigation of molecular approaches to control the exchange pathways in these dynamic assemblies.<br>

Computational insight into the cooperative role of non-covalent interactions in the aza-Henry reaction catalyzed by quinine derivatives: mechanism and enantioselectivity

2016 ◽  
Vol 14 (40) ◽  
pp. 9588-9597 ◽  
Author(s):  
Yunsheng Xue ◽  
Yuhui Wang ◽  
Zhongyan Cao ◽  
Jian Zhou ◽  
Zhao-Xu Chen
Keyword(s):  
Hydrogen Bonding ◽  
Dft Calculations ◽  
Ion Pair ◽  
Henry Reaction ◽  
Brönsted Acid ◽  
Non Covalent Interactions ◽  
Dual Activation ◽  
Covalent Interactions ◽  
Insight Into

DFT calculations reveal the viability of the two possible ion pair-hydrogen bonding and Brønsted acid-hydrogen bonding dual activation modes.

scholarly journals Columnar Aggregates of Azobenzene Stars: Exploring Intermolecular Interactions, Structure, and Stability in Atomistic Simulations

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7598
Author(s):  
Markus Koch ◽  
Marina Saphiannikova ◽  
Olga Guskova
Keyword(s):  
Hydrogen Bonds ◽  
Md Simulations ◽  
Binding Energies ◽  
Atomistic Simulations ◽  
Π Interactions ◽  
Different Types ◽  
Non Covalent Interactions ◽  
Experimental Works ◽  
Supramolecular Aggregates ◽  
Covalent Interactions

We present a simulation study of supramolecular aggregates formed by three-arm azobenzene (Azo) stars with a benzene-1,3,5-tricarboxamide (BTA) core in water. Previous experimental works by other research groups demonstrate that such Azo stars assemble into needle-like structures with light-responsive properties. Disregarding the response to light, we intend to characterize the equilibrium state of this system on the molecular scale. In particular, we aim to develop a thorough understanding of the binding mechanism between the molecules and analyze the structural properties of columnar stacks of Azo stars. Our study employs fully atomistic molecular dynamics (MD) simulations to model pre-assembled aggregates with various sizes and arrangements in water. In our detailed approach, we decompose the binding energies of the aggregates into the contributions due to the different types of non-covalent interactions and the contributions of the functional groups in the Azo stars. Initially, we investigate the origin and strength of the non-covalent interactions within a stacked dimer. Based on these findings, three arrangements of longer columnar stacks are prepared and equilibrated. We confirm that the binding energies of the stacks are mainly composed of π–π interactions between the conjugated parts of the molecules and hydrogen bonds formed between the stacked BTA cores. Our study quantifies the strength of these interactions and shows that the π–π interactions, especially between the Azo moieties, dominate the binding energies. We clarify that hydrogen bonds, which are predominant in BTA stacks, have only secondary energetic contributions in stacks of Azo stars but remain necessary stabilizers. Both types of interactions, π–π stacking and H-bonds, are required to maintain the columnar arrangement of the aggregates.

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