Predicting the Impact of Missense Mutations on Protein–Protein Binding Affinity

Modeling the impact of amino acid mutations on protein-protein interaction plays a crucial role in protein engineering and drug design. In this study, we develop GeoPPI, a novel structure-based deep-learning framework to predict the change of binding affinity upon mutations. Based on the three-dimensional structure of a protein, GeoPPI first learns a geometric representation that encodes topology features of the protein structure via a self-supervised learning scheme. These representations are then used as features for training gradient-boosting trees to predict the changes of protein-protein binding affinity upon mutations. We find that GeoPPI is able to learn meaningful features that characterize interactions between atoms in protein structures. In addition, through extensive experiments, we show that GeoPPI achieves new state-of-the-art performance in predicting the binding affinity changes upon both single- and multi-point mutations on six benchmark datasets. Moreover, we show that GeoPPI can accurately estimate the difference of binding affinities between a few recently identified SARS-CoV-2 antibodies and the receptor-binding domain (RBD) of the S protein. These results demonstrate the potential of GeoPPI as a powerful and useful computational tool in protein design and engineering. Our code and datasets are available at: https://github.com/Liuxg16/GeoPPI.

Download Full-text

SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

International Journal of Molecular Sciences ◽

10.3390/ijms222212114 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12114

Author(s):

Lin Yang ◽

Jiacheng Li ◽

Shuai Guo ◽

Chengyu Hou ◽

Chenchen Liao ◽

...

Keyword(s):

Binding Affinity ◽

Protein Complexes ◽

Amino Acid Position ◽

Protein Docking ◽

Binding Energies ◽

Missense Mutations ◽

Vaccination Rates ◽

Almost All ◽

The Impact ◽

Compensation Rule

Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.

Download Full-text

Faculty Opinions recommendation of Local Interaction Signal Analysis Predicts Protein-Protein Binding Affinity.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733279868.793547670 ◽

2018 ◽

Author(s):

Alexandre Bonvin

Keyword(s):

Protein Binding ◽

Binding Affinity ◽

Signal Analysis ◽

Local Interaction

Download Full-text

A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

Current Drug Discovery Technologies ◽

10.2174/1570163817666200827112252 ◽

2020 ◽

Vol 17 ◽

Author(s):

Suman Rohilla ◽

Ranju Bansal ◽

Puneet Chauhan ◽

Sonja Kachler ◽

Karl-Norbert Klotz

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Docking ◽

Binding Affinity ◽

Docking Studies ◽

Binding Modes ◽

Molecular Docking Studies ◽

In Silico Docking ◽

Adenosine A2a Receptor Antagonists ◽

The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Download Full-text

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured Versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study

Antibiotics ◽

10.3390/antibiotics10050557 ◽

2021 ◽

Vol 10 (5) ◽

pp. 557

Author(s):

Matthias Gijsen ◽

Erwin Dreesen ◽

Ruth Van Daele ◽

Pieter Annaert ◽

Yves Debaveye ◽

...

Keyword(s):

Renal Function ◽

Cohort Study ◽

Protein Binding ◽

Critically Ill ◽

Critically Ill Patients ◽

Observational Cohort Study ◽

Target Attainment ◽

Binding Model ◽

Observational Cohort ◽

The Impact

The impact of ceftriaxone pharmacokinetic alterations on protein binding and PK/PD target attainment still remains unclear. We evaluated pharmacokinetic/pharmacodynamic (PK/PD) target attainment of unbound ceftriaxone in critically ill patients with severe community-acquired pneumonia (CAP). Besides, we evaluated the accuracy of predicted vs. measured unbound ceftriaxone concentrations, and its impact on PK/PD target attainment. A prospective observational cohort study was carried out in adult patients admitted to the intensive care unit with severe CAP. Ceftriaxone 2 g q24h intermittent infusion was administered to all patients. Successful PK/PD target attainment was defined as unbound trough concentrations above 1 or 4 mg/L throughout the whole dosing interval. Acceptable overall PK/PD target attainment was defined as successful target attainment in ≥90% of all dosing intervals. Measured unbound ceftriaxone concentrations (CEFu) were compared to unbound concentrations predicted from various protein binding models. Thirty-one patients were included. The 1 mg/L and 4 mg/L targets were reached in 26/32 (81%) and 15/32 (47%) trough samples, respectively. Increased renal function was associated with the failure to attain both PK/PD targets. Unbound ceftriaxone concentrations predicted by the protein binding model developed in the present study showed acceptable bias and precision and had no major impact on PK/PD target attainment. We showed suboptimal (i.e., <90%) unbound ceftriaxone PK/PD target attainment when using a standard 2 g q24h dosing regimen in critically ill patients with severe CAP. Renal function was the major driver for the failure to attain the predefined targets, in accordance with results found in general and septic ICU patients. Interestingly, CEFu was reliably predicted from CEFt without major impact on clinical decisions regarding PK/PD target attainment. This suggests that, when carefully selecting a protein binding model, CEFu does not need to be measured. As a result, the turn-around time and cost for ceftriaxone quantification can be substantially reduced.

Download Full-text

Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites

Blood ◽

10.1182/blood-2007-08-108068 ◽

2008 ◽

Vol 111 (7) ◽

pp. 3468-3478 ◽

Cited By ~ 10

Author(s):

Adoración Venceslá ◽

María Ángeles Corral-Rodríguez ◽

Manel Baena ◽

Mónica Cornet ◽

Montserrat Domènech ◽

...

Keyword(s):

Hemophilia A ◽

Low Density Lipoprotein ◽

Scavenger Receptor ◽

Density Lipoprotein ◽

Missense Mutations ◽

Factor X ◽

Novel Mutations ◽

Large Deletions ◽

Function Relationship ◽

The Impact

Abstract Hemophilia A (HA) is an X-linked bleeding disorder caused by a wide variety of mutations in the factor 8 (F8) gene, leading to absent or deficient factor VIII (FVIII). We analyzed the F8 gene of 267 unrelated Spanish patients with HA. After excluding patients with the common intron-1 and intron-22 inversions and large deletions, we detected 137 individuals with small mutations, 31 of which had not been reported previously. Eleven of these were nonsense, frameshift, and splicing mutations, whereas 20 were missense changes. We assessed the impact of the 20 substitutions based on currently available information about FV and FVIII structure and function relationship, including previously reported results of replacements at these and topologically equivalent positions. Although most changes are likely to cause gross structural perturbations and concomitant cofactor instability, p.Ala375Ser is predicted to affect cofactor activation. Finally, 3 further mutations (p.Pro64Arg, p.Gly494Val, and p.Asp2267Gly) appear to affect cofactor interactions with its carrier protein, von Willebrand factor, with the scavenger receptor low-density lipoprotein receptor–related protein (LRP), and/or with the substrate of the FVIIIapi•FIXa (Xase) complex, factor X. Characterization of these novel mutations is important for adequate genetic counseling in HA families, but also contributes to a better understanding of FVIII structure-function relationship.

Download Full-text

Learning protein binding affinity using privileged information

BMC Bioinformatics ◽

10.1186/s12859-018-2448-z ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 6

Author(s):

Wajid Arshad Abbasi ◽

Amina Asif ◽

Asa Ben-Hur ◽

Fayyaz ul Amir Afsar Minhas

Keyword(s):

Protein Binding ◽

Binding Affinity ◽

Privileged Information

Download Full-text

In Planta Mutagenesis Determines the Functional Regions of the Wheat Puroindoline Proteins

Genetics ◽

10.1534/genetics.109.106013 ◽

2009 ◽

Vol 183 (3) ◽

pp. 853-860 ◽

Cited By ~ 31

Author(s):

Leila Feiz ◽

Brian S. Beecher ◽

John M. Martin ◽

Michael J. Giroux

Keyword(s):

Functional Analysis ◽

Allelic Variation ◽

Screening Method ◽

Point Mutations ◽

Missense Mutations ◽

Grain Hardness ◽

In Planta ◽

Rich Region ◽

Critical Function ◽

The Impact

In planta analysis of protein function in a crop plant could lead to improvements in understanding protein structure/function relationships as well as selective agronomic or end product quality improvements. The requirements for successful in planta analysis are a high mutation rate, an efficient screening method, and a trait with high heritability. Two ideal targets for functional analysis are the Puroindoline a and Puroindoline b (Pina and Pinb, respectively) genes, which together compose the wheat (Triticum aestivum L.) Ha locus that controls grain texture and many wheat end-use properties. Puroindolines (PINs) together impart soft texture, and mutations in either PIN result in hard seed texture. Studies of the PINs' mode of action are limited by low allelic variation. To create new Pin alleles and identify critical function-determining regions, Pin point mutations were created in planta via EMS treatment of a soft wheat. Grain hardness of 46 unique PIN missense alleles was then measured using segregating F2:F3 populations. The impact of individual missense alleles upon PIN function, as measured by grain hardness, ranged from neutral (74%) to intermediate to function abolishing. The percentage of function-abolishing mutations among mutations occurring in both PINA and PINB was higher for PINB, indicating that PINB is more critical to overall Ha function. This is contrary to expectations in that PINB is not as well conserved as PINA. All function-abolishing mutations resulted from structure-disrupting mutations or from missense mutations occurring near the Tryptophan-rich region. This study demonstrates the feasibility of in planta functional analysis of wheat proteins and that the Tryptophan-rich region is the most important region of both PINA and PINB.

Download Full-text

Evaluation for Protein Binding Affinity of Maghemite and Magnetite Nanoparticles

Journal of Nanoscience and Nanotechnology ◽

10.1166/jnn.2007.022 ◽

2007 ◽

Vol 7 (11) ◽

pp. 3706-3708 ◽

Cited By ~ 9

Author(s):

Se Chan Kang ◽

Yong Jun Jo ◽

Jong Phil Bak ◽

Ki-Chul Kim ◽

Young-Sung Kim

Keyword(s):

Protein Binding ◽

Binding Affinity ◽

Magnetite Nanoparticles ◽

Polyacrylamide Gel Electrophoresis ◽

Sodium Dodecyl ◽

Human Lung Cancer ◽

Maghemite Nanoparticles ◽

Binding Ability ◽

Sds Page ◽

Lung Cancer A549 Cell

We investigated the protein binding affinity of magnetite (Fe3O4) and maghemite (γ-Fe2O3) nanoparticles with against non-characterized protein from human lung cancer A549 cell line on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The binding ability of maghemite was 400 ng/mg. According to the SDS-PAGE results, the protein binding affinity of maghemite nanoparticles is stronger than magnetite nanoparticles. These data suggest that a protein can be detected with maghemite nanoparticles.

Download Full-text