scholarly journals Prediction of protein-protein interactions by combining structure and sequence conservation in protein interfaces

2005 ◽  
Vol 21 (12) ◽  
pp. 2850-2855 ◽  
Author(s):  
A. S. Aytuna ◽  
A. Gursoy ◽  
O. Keskin
Keyword(s):  
Protein Interactions ◽  
Sequence Conservation ◽  
Protein Protein Interactions ◽  
Protein Interfaces

scholarly journals Engineering selective competitors for the discrimination of highly conserved protein-protein interaction modules

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Charlotte Rimbault ◽  
Kashyap Maruthi ◽  
Christelle Breillat ◽  
Camille Genuer ◽  
Sara Crespillo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Pdz Domain ◽  
Specific Inhibitor ◽  
Rational Approach ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Domain Specific ◽  
Postsynaptic Protein ◽  
Protein Interfaces ◽  
Direct Generation

Abstract Designing highly specific modulators of protein-protein interactions (PPIs) is especially challenging in the context of multiple paralogs and conserved interaction surfaces. In this case, direct generation of selective and competitive inhibitors is hindered by high similarity within the evolutionary-related protein interfaces. We report here a strategy that uses a semi-rational approach to separate the modulator design into two functional parts. We first achieve specificity toward a region outside of the interface by using phage display selection coupled with molecular and cellular validation. Highly selective competition is then generated by appending the more degenerate interaction peptide to contact the target interface. We apply this approach to specifically bind a single PDZ domain within the postsynaptic protein PSD-95 over highly similar PDZ domains in PSD-93, SAP-97 and SAP-102. Our work provides a paralog-selective and domain specific inhibitor of PSD-95, and describes a method to efficiently target other conserved PPI modules.

Prediction of protein–protein interactions: unifying evolution and structure at protein interfaces

2011 ◽  
Vol 8 (3) ◽  
pp. 035006 ◽  
Author(s):  
Nurcan Tuncbag ◽  
Attila Gursoy ◽  
Ozlem Keskin
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Protein Interfaces

scholarly journals Conservation of coevolving protein interfaces bridges prokaryote–eukaryote homologies in the twilight zone

2016 ◽  
Vol 113 (52) ◽  
pp. 15018-15023 ◽  
Author(s):  
Juan Rodriguez-Rivas ◽  
Simone Marsili ◽  
David Juan ◽  
Alfonso Valencia
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Accurate Information ◽  
Twilight Zone ◽  
Sequence Information ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Protein Interfaces ◽  
Recent Developments

Protein–protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue coevolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that coevolution points to structurally conserved contacts at protein–protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a domain-centered protocol to study the interplay between residue coevolution and structural conservation of protein–protein interfaces. We show that sequence-based coevolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein–protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence (the twilight zone), where standard homology modeling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic coevolutionary analysis to the prediction of eukaryotic interfaces further illustrate the potential of this approach.

scholarly journals Variables Influencing Differences in Sequence Conservation in the Fission Yeast Schizosaccharomyces pombe

2021 ◽  
Author(s):  
Simon Emanuel Harnqvist ◽  
Cooper Alastair Grace ◽  
Daniel Charlton Jeffares
Keyword(s):  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Protein Interactions ◽  
Model Organism ◽  
Sequence Conservation ◽  
Rate Variation ◽  
Sequence Evolution ◽  
Least Squares Regression ◽  
Protein Protein Interactions ◽  
Partial Correlations

AbstractWhich variables determine the constraints on gene sequence evolution is one of the most central questions in molecular evolution. In the fission yeast Schizosaccharomyces pombe, an important model organism, the variables influencing the rate of sequence evolution have yet to be determined. Previous studies in other single celled organisms have generally found gene expression levels to be most significant, with numerous other variables such as gene length and functional importance identified as having a smaller impact. Using publicly available data, we used partial least squares regression, principal components regression, and partial correlations to determine the variables most strongly associated with sequence evolution constraints. We identify centrality in the protein–protein interactions network, amino acid composition, and cellular location as the most important determinants of sequence conservation. However, each factor only explains a small amount of variance, and there are numerous variables having a significant or heterogeneous influence. Our models explain more than half of the variance in dN, raising the possibility that future refined models could quantify the role of stochastics in evolutionary rate variation.

scholarly journals Structural and Computational Characterization of Disease-Related Mutations Involved in Protein-Protein Interfaces

2019 ◽  
Vol 20 (7) ◽  
pp. 1583 ◽  
Author(s):  
Dàmaris Navío ◽  
Mireia Rosell ◽  
Josu Aguirre ◽  
Xavier de la Cruz ◽  
Juan Fernández-Recio
Keyword(s):  
Protein Interactions ◽  
Computational Analysis ◽  
Molecular Level ◽  
Binding Free Energy ◽  
Evolutionary Conservation ◽  
Core Region ◽  
Protein Protein Interactions ◽  
The Core ◽  
Protein Interfaces

One of the known potential effects of disease-causing amino acid substitutions in proteins is to modulate protein-protein interactions (PPIs). To interpret such variants at the molecular level and to obtain useful information for prediction purposes, it is important to determine whether they are located at protein-protein interfaces, which are composed of two main regions, core and rim, with different evolutionary conservation and physicochemical properties. Here we have performed a structural, energetics and computational analysis of interactions between proteins hosting mutations related to diseases detected in newborn screening. Interface residues were classified as core or rim, showing that the core residues contribute the most to the binding free energy of the PPI. Disease-causing variants are more likely to occur at the interface core region rather than at the interface rim (p < 0.0001). In contrast, neutral variants are more often found at the interface rim or at the non-interacting surface rather than at the interface core region. We also found that arginine, tryptophan, and tyrosine are over-represented among mutated residues leading to disease. These results can enhance our understanding of disease at molecular level and thus contribute towards personalized medicine by helping clinicians to provide adequate diagnosis and treatments.

scholarly journals Conservation of co-evolving protein interfaces bridges prokaryote-eukaryote homologies in the twilight zone

2016 ◽  
Author(s):  
Juan Rodriguez-Rivas ◽  
Simone Marsili ◽  
David Juan ◽  
Alfonso Valencia
Keyword(s):  
Protein Interactions ◽  
Homology Modelling ◽  
Accurate Information ◽  
Sequence Information ◽  
Evolutionary Analysis ◽  
Interacting Proteins ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Protein Interfaces

AbstractProtein-protein interactions are fundamental for the proper functioning of the cell. As a result, protein interaction surfaces are subject to strong evolutionary constraints. Recent developments have shown that residue co-evolution provides accurate predictions of heterodimeric protein interfaces from sequence information. So far these approaches have been limited to the analysis of families of prokaryotic complexes for which large multiple sequence alignments of homologous sequences can be compiled. We explore the hypothesis that co-evolution points to structurally conserved contacts at protein-protein interfaces, which can be reliably projected to homologous complexes with distantly related sequences. We introduce a novel domain-centred protocol to study the interplay between residue co-evolution and structural conservation of protein-protein interfaces. We show that sequence-based co-evolutionary analysis systematically identifies residue contacts at prokaryotic interfaces that are structurally conserved at the interface of their eukaryotic counterparts. In turn, this allows the prediction of conserved contacts at eukaryotic protein-protein interfaces with high confidence using solely mutational patterns extracted from prokaryotic genomes. Even in the context of high divergence in sequence, where standard homology modelling of protein complexes is unreliable, our approach provides sequence-based accurate information about specific details of protein interactions at the residue level. Selected examples of the application of prokaryotic co-evolutionary analysis to the prediction of eukaryotic interfaces further illustrates the potential of this novel approach.Significance statementInteracting proteins tend to co-evolve through interdependent changes at the interaction interface. This phenomenon leads to patterns of coordinated mutations that can be exploited to systematically predict contacts between interacting proteins in prokaryotes. We explore the hypothesis that co-evolving contacts at protein interfaces are preferentially conserved through long evolutionary periods. We demonstrate that co-evolving residues in prokaryotes identify inter-protein contacts that are particularly well conserved in the corresponding structure of their eukaryotic homologues. Therefore, these contacts have likely been important to maintain protein-protein interactions during evolution. We show that this property can be used to reliably predict interacting residues between eukaryotic proteins with homologues in prokaryotes even if they are very distantly related in sequence.

A structural network associated with the kallikrein-kinin and renin-angiotensin systems

2010 ◽  
Vol 391 (4) ◽  
Author(s):  
Veronika Stoka ◽  
Vito Turk
Keyword(s):  
Protein Interactions ◽  
Three Dimensional ◽  
Type I ◽  
Protein Protein Interactions ◽  
Renin Angiotensin ◽  
Protein Protein Interaction ◽  
Protein Interfaces ◽  
Structural Network ◽  
Domain Interactions ◽  
Fibronectin Type

Abstract The kallikrein-kinin and renin-angiotensin (KKS-RAS) systems represent two highly regulated proteolytic systems that are involved in several physiological and pathological processes. Although their protein-protein interactions can be studied using experimental approaches, it is difficult to differentiate between direct physical interactions and functional associations, which do not involve direct atomic contacts between macromolecules. This information can be obtained from an atomic-resolution characterization of the protein interfaces. As a result of this, various three-dimensional-based protein-protein interaction databases have become available. To gain insight into the multilayered interaction of the KKS-RAS systems, we present a protein network that is built up on three-dimensional domain-domain interactions. The essential domains that link these systems are as follows: Cystatin, Peptidase_C1, Thyroglobulin_1, Insulin, CIMR (Cation-independent mannose-6-phosphate receptor repeat), fn2 (Fibronectin type II domain), fn1 (Fibronectin type I domain), EGF, Trypsin, and Serpin. We found that the CIMR domain is located at the core of the network, thus connecting both systems. From the latter, all domain interactors up to level 4 were retrieved, thus displaying a more comprehensive representation of the KKS-RAS structural network.

Predicting affinity- and specificity-enhancing mutations at protein–protein interfaces

2013 ◽  
Vol 41 (5) ◽  
pp. 1166-1169 ◽  
Author(s):  
Oz Sharabi ◽  
Jason Shirian ◽  
Julia M. Shifman
Keyword(s):  
Protein Interactions ◽  
Computational Method ◽  
Protein Protein Interactions ◽  
Binding Interface ◽  
Protein Interfaces ◽  
Molecular Forces ◽  
Free Energy Of Binding ◽  
Binding Interfaces ◽  
Snake Toxin ◽  
Computational Predictions

Manipulations of PPIs (protein–protein interactions) are important for many biological applications such as synthetic biology and drug design. Combinatorial methods have been traditionally used for such manipulations, failing, however, to explain the effects achieved. We developed a computational method for prediction of changes in free energy of binding due to mutation that bring about deeper understanding of the molecular forces underlying binding interactions. Our method could be used for computational scanning of binding interfaces and subsequent analysis of the interfacial sequence optimality. The computational method was validated in two biological systems. Computational saturated mutagenesis of a high-affinity complex between an enzyme AChE (acetylcholinesterase) and a snake toxin Fas (fasciculin) revealed the optimal nature of this interface with only a few predicted affinity-enhancing mutations. Binding measurements confirmed high optimality of this interface and identified a few mutations that could further improve interaction fitness. Computational interface scanning of a medium-affinity complex between TIMP-2 (tissue inhibitor of metalloproteinases-2) and MMP (matrix metalloproteinase) 14 revealed a non-optimal nature of the binding interface with multiple mutations predicted to stabilize the complex. Experimental results corroborated our computational predictions, identifying a large number of mutations that improve the binding affinity for this interaction and some mutations that enhance binding specificity. Overall, our computational protocol greatly facilitates the discovery of affinity- and specificity-enhancing mutations and thus could be applied for design of potent and highly specific inhibitors of any PPI.

scholarly journals Modulating Protein–Protein Interactions by Cyclic and Macrocyclic Peptides. Prominent Strategies and Examples

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 445
Author(s):  
Rosario González-Muñiz ◽  
María Ángeles Bonache ◽  
María Jesús Pérez de Vega
Keyword(s):  
Protein Interactions ◽  
Recent Progress ◽  
Cell Penetrating Peptides ◽  
Protein Protein Interactions ◽  
Future Mission ◽  
Protein Interfaces ◽  
Peptide Derivatives ◽  
Macrocyclic Peptides ◽  
Synthetic Methodologies ◽  
Macrocyclic Peptide

Cyclic and macrocyclic peptides constitute advanced molecules for modulating protein–protein interactions (PPIs). Although still peptide derivatives, they are metabolically more stable than linear counterparts, and should have a lower degree of flexibility, with more defined secondary structure conformations that can be adapted to imitate protein interfaces. In this review, we analyze recent progress on the main methods to access cyclic/macrocyclic peptide derivatives, with emphasis in a few selected examples designed to interfere within PPIs. These types of peptides can be from natural origin, or prepared by biochemical or synthetic methodologies, and their design could be aided by computational approaches. Some advances to facilitate the permeability of these quite big molecules by conjugation with cell penetrating peptides, and the incorporation of β-amino acid and peptoid structures to improve metabolic stability, are also commented. It is predicted that this field of research could have an important future mission, running in parallel to the discovery of new, relevant PPIs involved in pathological processes.

scholarly journals Residue–Residue Interaction Prediction via Stacked Meta-Learning

2021 ◽  
Vol 22 (12) ◽  
pp. 6393
Author(s):  
Kuan-Hsi Chen ◽  
Yuh-Jyh Hu
Keyword(s):  
Protein Interactions ◽  
Protein Complexes ◽  
Comparative Case Study ◽  
Protein Protein Interactions ◽  
Hierarchical Learning ◽  
Residue Interaction ◽  
Protein Interfaces ◽  
Multiple Feature ◽  
Meta Learning

Protein–protein interactions (PPIs) are the basis of most biological functions determined by residue–residue interactions (RRIs). Predicting residue pairs responsible for the interaction is crucial for understanding the cause of a disease and drug design. Computational approaches that considered inexpensive and faster solutions for RRI prediction have been widely used to predict protein interfaces for further analysis. This study presents RRI-Meta, an ensemble meta-learning-based method for RRI prediction. Its hierarchical learning structure comprises four base classifiers and one meta-classifier to integrate predictive strengths from different classifiers. It considers multiple feature types, including sequence-, structure-, and neighbor-based features, for characterizing other properties of a residue interaction environment to better distinguish between noninteracting and interacting residues. We conducted the same experiments using the same data as previously reported in the literature to demonstrate RRI-Meta’s performance. Experimental results show that RRI-Meta is superior to several current prediction tools. Additionally, to analyze the factors that affect the performance of RRI-Meta, we conducted a comparative case study using different protein complexes.

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