scholarly journals Cost function network-based design of protein–protein interactions: predicting changes in binding affinity

2018 ◽  
Vol 34 (15) ◽  
pp. 2581-2589 ◽  
Author(s):  
Clément Viricel ◽  
Simon de Givry ◽  
Thomas Schiex ◽  
Sophie Barbe
Keyword(s):  
Cost Function ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Function Network

scholarly journals Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2216-2227 ◽  
Author(s):  
Wiktoria Jedwabny ◽  
Szymon Kłossowski ◽  
Trupta Purohit ◽  
Tomasz Cierpicki ◽  
Jolanta Grembecka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Empirical Model ◽  
Inhibitory Activity ◽  
Theoretical Models ◽  
Mixed Lineage Leukemia ◽  
Protein Protein Interactions ◽  
Model Based ◽  
Dispersion Terms

A computationally affordable, non-empirical model based on electrostatic multipole and dispersion terms successfully predicts the binding affinity of inhibitors of menin–MLL protein–protein interactions.

scholarly journals Engineered pH-Sensitive Protein G / IgG Interaction

2020 ◽  
Author(s):  
Ramesh K. Jha ◽  
Allison Yankey ◽  
Kalifa Shabazz ◽  
Leslie Naranjo ◽  
Nileena Velappan ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Design ◽  
Protein Interactions ◽  
Rational Design ◽  
Protein G ◽  
Acidic Ph ◽  
Protein Protein Interactions ◽  
Natural Interface ◽  
Complex Stimuli ◽  
Igg Purification

ABSTRACTWhile natural protein-protein interactions have evolved to be induced by complex stimuli, rational design of interactions that can be switched-on-demand still remain challenging in the protein design world. Here, we demonstrate a computationally redesigned natural interface for improved binding affinity could further be mutated to adopt a pH switchable interaction. The redesigned interface of Protein G-IgG Fc domain, when incorporated with histidine and glutamic acid on Protein G (PrG-EHHE), showed a switch in binding affinity by 50-fold when pH was altered from mild acidic to mild basic. The wild type (WT) interface only showed negligible switch. The overall binding affinity at mild acidic pH for PrG-EHHE outperformed the WT PrG interaction. The new reagent PrG-EHHE will be revolutionary in IgG purification since the traditional method of using an extreme acidic pH for elution can be circumvented.Abstract Figure

scholarly journals Engineering an improved light-induced dimer (iLID) for controlling the localization and activity of signaling proteins

2014 ◽  
Vol 112 (1) ◽  
pp. 112-117 ◽  
Author(s):  
Gurkan Guntas ◽  
Ryan A. Hallett ◽  
Seth P. Zimmerman ◽  
Tishan Williams ◽  
Hayretin Yumerefendi ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Design ◽  
Protein Interactions ◽  
Mammalian Cell Culture ◽  
Large Change ◽  
Small Gtpase ◽  
Protein Protein Interactions ◽  
Binding Assays ◽  
Light Stimulation ◽  
Inducible Protein

The discovery of light-inducible protein–protein interactions has allowed for the spatial and temporal control of a variety of biological processes. To be effective, a photodimerizer should have several characteristics: it should show a large change in binding affinity upon light stimulation, it should not cross-react with other molecules in the cell, and it should be easily used in a variety of organisms to recruit proteins of interest to each other. To create a switch that meets these criteria we have embedded the bacterial SsrA peptide in the C-terminal helix of a naturally occurring photoswitch, the light-oxygen-voltage 2 (LOV2) domain from Avena sativa. In the dark the SsrA peptide is sterically blocked from binding its natural binding partner, SspB. When activated with blue light, the C-terminal helix of the LOV2 domain undocks from the protein, allowing the SsrA peptide to bind SspB. Without optimization, the switch exhibited a twofold change in binding affinity for SspB with light stimulation. Here, we describe the use of computational protein design, phage display, and high-throughput binding assays to create an improved light inducible dimer (iLID) that changes its affinity for SspB by over 50-fold with light stimulation. A crystal structure of iLID shows a critical interaction between the surface of the LOV2 domain and a phenylalanine engineered to more tightly pin the SsrA peptide against the LOV2 domain in the dark. We demonstrate the functional utility of the switch through light-mediated subcellular localization in mammalian cell culture and reversible control of small GTPase signaling.

scholarly journals Quantitative yeast-yeast two hybrid for discovery and binding affinity estimation of protein-protein interactions

2020 ◽  
Author(s):  
Kaitlyn Bacon ◽  
Abigail Blain ◽  
John Bowen ◽  
Matthew Burroughs ◽  
Nikki McArthur ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Quantitative Estimation ◽  
Surface Display ◽  
Combinatorial Libraries ◽  
Yeast Surface Display ◽  
Binding Affinities ◽  
Protein Protein Interactions ◽  
Yeast Two Hybrid ◽  
Two Hybrid

AbstractQuantifying the binding affinity of protein-protein interactions is important for elucidating connections within biochemical signaling pathways, as well as characterization of binding proteins isolated from combinatorial libraries. We describe a quantitative yeast-yeast two hybrid (qYY2H) system that not only enables discovery of specific protein-protein interactions, but also efficient, quantitative estimation of their binding affinities (KD). In qYY2H, the bait and prey proteins are expressed as yeast cell surface fusions using yeast surface display. We developed a semi-empirical framework for estimating the KD of monovalent bait-prey interactions, using measurements of the apparent KD of yeast-yeast binding, which is mediated by multivalent interactions between yeast-displayed bait and prey. Using qYY2H, we identified interaction partners of SMAD3 and the tandem WW domains of YAP from a cDNA library and characterized their binding affinities. Finally, we showed that qYY2H could also quantitatively evaluate binding interactions mediated by post-translational modifications on the bait protein.

Protein–protein interactions: scoring schemes and binding affinity

2017 ◽  
Vol 44 ◽  
pp. 31-38 ◽  
Author(s):  
M Michael Gromiha ◽  
K Yugandhar ◽  
Sherlyn Jemimah
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Scoring Schemes

scholarly journals Contacts-based prediction of binding affinity in protein–protein complexes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Anna Vangone ◽  
Alexandre MJJ Bonvin
Keyword(s):  
Binding Affinity ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Prediction Accuracy ◽  
Protein Complexes ◽  
Structural Features ◽  
Specific Protein ◽  
Strong Impact ◽  
Protein Protein Interactions ◽  
Almost All

Almost all critical functions in cells rely on specific protein–protein interactions. Understanding these is therefore crucial in the investigation of biological systems. Despite all past efforts, we still lack a thorough understanding of the energetics of association of proteins. Here, we introduce a new and simple approach to predict binding affinity based on functional and structural features of the biological system, namely the network of interfacial contacts. We assess its performance against a protein–protein binding affinity benchmark and show that both experimental methods used for affinity measurements and conformational changes have a strong impact on prediction accuracy. Using a subset of complexes with reliable experimental binding affinities and combining our contacts and contact-types-based model with recent observations on the role of the non-interacting surface in protein–protein interactions, we reach a high prediction accuracy for such a diverse dataset outperforming all other tested methods.

scholarly journals Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site

2021 ◽  
Author(s):  
Shiran Lacham-Hartman ◽  
Yulia Shmidov ◽  
Evette S. Radisky ◽  
Ronit Bitton ◽  
David B. Lukatsky ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Protein Complex ◽  
Binding Sites ◽  
Biological Interactions ◽  
Protein Protein Interactions ◽  
Regulatory Pathways ◽  
Multiple Binding Sites ◽  
Ligand Binding Sites

AbstractAlthough myriad protein–protein interactions in nature use polyvalent binding, in which multiple ligands on one entity bind to multiple receptors on another, to date an affinity advantage of polyvalent binding has been demonstrated experimentally only in cases where the target receptor molecules are clustered prior to complex formation. Here, we demonstrate cooperativity in binding affinity (i.e., avidity) for a protein complex in which an engineered dimer of the amyloid precursor protein inhibitor (APPI), possessing two fully functional inhibitory loops, interacts with mesotrypsin, a soluble monomeric protein that does not self-associate or cluster spontaneously. We found that each inhibitory loop of the purified APPI homodimer was over three-fold more potent than the corresponding loop in the monovalent APPI inhibitor. This observation is consistent with a suggested mechanism whereby the two APPI loops in the homodimer simultaneously and reversibly bind two corresponding mesotrypsin monomers to mediate mesotrypsin dimerization. We propose a simple model for such dimerization that quantitatively explains the observed cooperativity in binding affinity. Binding cooperativity in this system reveals that the valency of ligands may affect avidity in protein–protein interactions including those of targets that are not surface-anchored and do not self-associate spontaneously. In this scenario, avidity may be explained by the enhanced concentration of ligand binding sites in proximity to the monomeric target, which may favor rebinding of the multiple ligand binding sites with the receptor molecules upon dissociation of the protein complex.Impact statementLacham-Hartman et al. demonstrate enhancement of binding affinity through avidity in a complex between a bivalent ligand and a soluble monomeric target with a single binding site. Avidity effects have previously been demonstrated only for clustered receptor molecules presenting multiple binding sites. Our model may explain how polyvalent ligands can agonize or antagonize biological interactions involving nonclustered target molecules that are crucial for intra- and extracellular structural, metabolic, signaling, and regulatory pathways.

scholarly journals Mining peptides against SARS-CoV-2 entry from constructed RBMs-hACE2 isomer libraries using machine learning and molecular docking

2020 ◽  
Author(s):  
Xiaotong He
Keyword(s):  
Binding Affinity ◽  
Protein Interactions ◽  
Surface Protein ◽  
Protein S ◽  
Protein Protein Interactions ◽  
Angiotensin Converting Enzyme 2 ◽  
Transmembrane Potentials ◽  
Inhibitory Peptides ◽  
Feature Filters

Abstract Cellular entry of SARS-CoV-2 initiates from the protein-protein interactions (PPIs) between viral surface protein S and human angiotensin converting enzyme 2 (hACE2). Peptide-based drugs have the advantage of small molecule compounds to block such viral-host PPIs. Thus the viral targetregions on hACE2 have been believed as promising templates for designing specific inhibitory peptides against SARS-CoV-2 infection. However, starting from a few potential templates, in silico design and prediction between binding affinity and bioactivities in vivo are very challenging, herein a novel design strategy was implemented by mining constructed template isomer libraries using feature filters, supervised classifier and peptide protein docking.Applying these methods and the isomer libraries, 4 peptides were identified from 12 millions candidates owing to their distinct stability, interaction activity, inhibitory specificity, binding affinity, transmembrane potentials and effective conformation. These results have supplied a panel of specific anti-COVID19 leads for further drug development, supporting a new feasible antiviral strategy for targeting both intracellular and extracellular SARS-CoV-2 S proteins simultaneously. The methods have provided a useful tool for mining antiviral-peptides against viral diseases.

scholarly journals A Comprehensive Review on Current Advances in Peptide Drug Development and Design

2019 ◽  
Vol 20 (10) ◽  
pp. 2383 ◽  
Author(s):  
Andy Chi-Lung Lee ◽  
Janelle Louise Harris ◽  
Kum Kum Khanna ◽  
Ji-Hong Hong
Keyword(s):  
Drug Development ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Binding Sites ◽  
Drug Targets ◽  
Peptide Drug ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Endogenous Protein ◽  
Binding Interfaces

Protein–protein interactions (PPIs) execute many fundamental cellular functions and have served as prime drug targets over the last two decades. Interfering intracellular PPIs with small molecules has been extremely difficult for larger or flat binding sites, as antibodies cannot cross the cell membrane to reach such target sites. In recent years, peptides smaller size and balance of conformational rigidity and flexibility have made them promising candidates for targeting challenging binding interfaces with satisfactory binding affinity and specificity. Deciphering and characterizing peptide–protein recognition mechanisms is thus central for the invention of peptide-based strategies to interfere with endogenous protein interactions, or improvement of the binding affinity and specificity of existing approaches. Importantly, a variety of computation-aided rational designs for peptide therapeutics have been developed, which aim to deliver comprehensive docking for peptide–protein interaction interfaces. Over 60 peptides have been approved and administrated globally in clinics. Despite this, advances in various docking models are only on the merge of making their contribution to peptide drug development. In this review, we provide (i) a holistic overview of peptide drug development and the fundamental technologies utilized to date, and (ii) an updated review on key developments of computational modeling of peptide–protein interactions (PepPIs) with an aim to assist experimental biologists exploit suitable docking methods to advance peptide interfering strategies against PPIs.

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