Predicting binding poses and affinities for protein-ligand complexes in the 2015 D3R Grand Challenge using a physical model with a statistical parameter estimation

International audienceThe 2015 D3R Grand Challenge provided an opportunity to test our new model for the binding free energy of small molecules, as well as to assess our protocol to predict binding poses for protein-ligand complexes. Our pose predictions were ranked 3-9 for the HSP90 dataset, depending on the assessment metric. For the MAP4K dataset the ranks are very dispersed and equal to 2-35, depending on the assessment metric, which does not provide any insight into the accuracy of the method. The main success of our pose prediction protocol was the re-scoring stage using the recently developed Convex-PL potential. We make a thorough analysis of our docking predictions made with AutoDock Vina and discuss the effect of the choice of rigid receptor templates, the number of flexible residues in the binding pocket, the binding pocket size, and the benefits of re-scoring. However, the main challenge was to predict experimentally determined binding affinities for two blind test sets. Our affinity prediction model consisted of two terms, a pairwise-additive enthalpy, and a non pairwise-additive entropy. We trained the free parameters of the model with a regularized regression using affinity and structural data from the PDBBind database. Our model performed very well on the training set, however, failed on the two test sets. We explain the drawback and pitfalls of our model, in particular in terms of relative coverage of the test set by the training set and missed dynamical properties from crystal structures, and discuss different routes to improve it

High Resolution Crystal Structures Leverage Protein Binding Affinity Predictions

Predicting protein binding affinities from structural data has remained elusive, adifficulty owing to the variety of protein binding modes. Using the structure-affinity-benchmark(SAB, 144 cases with bound/unbound crystal structures and experimental affinity measurements),prediction has been undertaken either by fitting a model using a handfull of pre-defined variables,or by training a complex model from a large pool of parameters (typically hundreds). The formerroute unnecessarily restricts the model space, while the latter is prone to overfitting.We design models in a third tier, using twelve variables describing enthalpic and entropic variationsupon binding, and a model selection procedure identifying the best sparse model built from a subsetof these variables. Using these models, we report three main results. First, we present modelsyielding a marked improvement of affinity predictions. For the whole dataset, we present a modelpredicting Kd within one and two orders of magnitude for 48% and 79% of cases, respectively.These statistics jump to 62% and 89% respectively, for the subset of the SAB consisting of highresolution structures. Second, we show that these performances owe to a new parameter encodinginterface morphology and packing properties of interface atoms. Third, we argue that interfaceflexibility and prediction hardness do not correlate, and that for flexible cases, a performancematching that of the whole SAB can be achieved. Overall, our work suggests that the affinityprediction problem could be partly solved using databases of high resolution complexes whoseaffinity is known

Prevalence of macular complications related to myopia – Results of a multicenter evaluation of myopic patients in eye clinics in France

Purpose: Uncorrected refractive errors are the first cause of vision impairment worldwide. High myopia is a frequent cause of sight‐threatening chorioretinal complications. The aim of this study was to evaluate the prevalence of macular complications, visual impairment and blindness in patients with myopia. Methods: A cross‐sectional multicenter study carried out in French eye clinics mainly dedicated to refractive errors. Myopia severity was defined as mild (−0.5 to −3 D), moderate (−3 to −6 D), high (−6 to −10 D) and very high (more than −10 D). Macular complications related to myopia included lacquer cracks, myopic choroidal neovascularization, chorioretinal atrophy and retinoschisis. The prevalences of macular complications, blindness and vision impairment were estimated with respect to degree of myopia and age. Eligibility criteria were myopia on the left eye of −0.5 D or more. Exclusion criteria included any missing data related to subjective refractive error, age, gender and any history of cataract or refractive surgery. Results: Data files from 198 641 myopic individuals with a mean age of 34 years (SD: 15 years) were analysed. The prevalence of mild, moderate, high and very high myopia was, respectively, 65.95%, 26.14%, 6.72% and 1.19%. The prevalence of macular complications in the high and very high myopia groups was 0.5% [0.39–0.64] and 4.27% [3.49–5.17]. The prevalence of blindness or vision impairment was observed in 10.10% [8.91–11.39%] of the very high myopic group. At 60 years old or over, the prevalences of blindness or vision impairment were, respectively, 9.75% [7.91–11.85%] and 25.71% [21.00–30.87%] in the high and very high myopia groups. Conclusions: This multicenter cross‐sectional study provides new insights in terms of prevalence of macular complications related to myopia. To our knowledge, this is one of the largest European studies focusing on individuals with myopia, particularly on the macular complications and the functional consequences in relation to myopia

Analyse des Interfaces de complexes Anticorps - Antigène: des caractéristiques propres au type de ligand à la prédiction d'affinité de liaison

Adaptive immunity is based on antigen-specific lymphocyte responses, with inparticular B cells secreting seric immunoglobulins (IG) involved in the opsonization of bacteriaand the neutralization of viruses. At the heart of these mechanisms is the formation of IG -Ag complexes, which challenge our understanding in terms of binding affinity and interactionspecificity.In this work, we dissect the interfaces of IG - Ag complexes with high resolution crystal structures,making a stride towards a better understanding of binding affinity and interaction specificity. First,we present global interface statistics clearly distinguishing ligand types (proteins, peptides, chem-ical compounds), and stressing the role of side chains. Second, we analyze the relative positions ofCDR with and without antigen, exhibiting a remarkably conserved pattern involving seven seamsbetween CDR. We also show that this generic pattern exhibits specific properties as a function ofthe ligand type. Finally, we present binding affinity predictions of unprecedented accuracy, with amedian absolute error of 1.02 kcal/mol.We anticipate that our findings will be of broad interest, not only in studying immune responsesat the structural level, but also in bio-engineering and IG design, with IG used extensively indiagnostics and as well as therapeutic agents

Progression of myopia in teenagers and adults: a nationwide longitudinal study of a prevalent cohort

Background- The prevalence of myopia is increasing worldwide. The purpose of this study was to evaluate the progression of myopia in teenagers and adults in France. Methods- This nationwide prospective study followed 630 487 myopic adults and teenagers (mean age 43.4 years±18.2, 59.8% of women) between January 2013 and January 2019. Myopia and high myopia were defined as a spherical equivalent less than or equal to –0.50 and –6.00 diopters (D), respectively. Demographic data were collected at first visit and refractive characteristics were collected at each visit. Analysis of short-term progression (first 12 to 26 months postbaseline) was modelled using analysis of variance (ANOVA). Progression of myopia was stratified according to age, gender and spherical equivalent at first visit. Results- Higher proportions of progressors were observed in the youngest age groups: 14–15 (18.2 %) and 16–17 years old (13.9 %). In multivariate analysis, after adjustment for over age, spherical equivalent and gender, the mean short-term progression decreased from –0.36 D in the 14–15 years age group to –0.13 D in the 28–29 years age group. Young age and higher myopia at baseline together were strongly associated with the risk of developing high myopia, the 5-year cumulative risk being 76% for youngest teenager with higher myopia status at baseline. Conclusion- In this large cohort of myopic teenagers and adults, myopia progression was reported in 18.2% and 13.9% of the 14–15 and 16–17 age groups, respectively. The risk to develop high myopia was higher for younger individuals with higher myopia at baseline examination

Progression of myopia in children and teenagers: a nationwide longitudinal study

Background: Data on myopia prevalence and progression in European children are sparse. The aim of this work was to evaluate the progression of myopia in children and teenagers in a large prospective study. Methods: A prospective study involving a nationwide cohort. Myopia was defined as a spherical equivalent (SE) of ≤ –0.50 diopters (D). Data on refractive error, gender and age were collected in 696 optical centres in France between 2013 and 2019, including 136 333 children (4–17 years old) in the analysis. Progression of myopia was assessed between the first visit and the last visit over up to 6.5 years. Results: Mean age was 11.3±3.8 years (55.0% of female). The proportion of children progressing more than –0.50 D per year was higher in age groups 7–9 years and 10–12 years and in children with SE ≤ –4.00 D at first visit, representing 33.1%, 29.4% and 30.0% of these groups, respectively. In multivariate analysis, progression during the first 11–24 months was higher in the 7–9 and 10–12 age groups (–0.43 D and –0.42 D, respectively), for higher SE at baseline (at least –0.33 D for SE ≤ –1 D) and for girls (–0.35 D). Conclusion: This is the first French epidemiological study to investigate myopia progression in a large-scale cohort of children. Sex, age groups and myopia severity are associated with differing rates of progression

Self-reported dual sensory impairment and related factors: a European population-based cross-sectional survey

International audienceBackground Data on population-based self-reported dual vision and hearing impairment are sparse in Europe. We aimed to investigate self-reported dual sensory impairment (DSI) in European population. Methods A standardised questionnaire was used to collect medical and socio-economic data among individuals aged 15 years or more in 29 European countries. Individuals living in collective households or in institutions were excluded from the survey. Results Among 296 677 individuals, the survey included 153 866 respondents aged 50 years old or more. The crude prevalence of DSI was of 7.54% (7.36–7.72). Among individuals aged 60 or more, 9.23% of men and 10.94% of women had DSI. Eastern and southern countries had a higher prevalence of DSI. Multivariable analyses showed that social isolation and poor self-rated health status were associated with DSI with ORs of 2.01 (1.77–2.29) and 2.33 (2.15–2.52), while higher income was associated with lower risk of DSI (OR of 0.83 (0.78–0.89). Considering country-level socioeconomic factors, Human Development Index explained almost 38% of the variance of age-adjusted prevalence of DSI. Conclusion There are important differences in terms of prevalence of DSI in Europe, depending on socioeconomic and medical factors. Prevention of DSI does represent an important challenge for maintaining quality of life in elderly population

Self-reported visual difficulties in Europe and related factors: a European population-based cross-sectional survey.

PURPOSE: There is a relative paucity of self-reported vision problems data in European countries. METHODS: In this context, we investigated self-reported vision problems through European Health Interview Survey 2, a cross-sectional European population survey based on a standardized questionnaire including 147 medical, demographic and socioeconomic variables applied to non-institutionalized individuals aged 15 years or more in 28 European countries, in addition to Iceland and Norway. RESULTS: The survey included 311 386 individuals (54.18% women), with overall crude prevalence of self-reported vision problems of 2.07% [95% CI; 2.01-2.14]. Among them, 1.70 % [1.61-1.78] of men, 2.41% [2.31-2.51] of women and 4.71% [4.53-4.89] of individuals aged 60 or more reported to have a lot of vision problems or to be not able to see. The frequency of self-reported vision problems was the highest in Eastern European countries with values of 2.43% [2.30-2.56]. In multivariate analyses, limiting long-standing illness, depression, daily smoking, lack of physical activity, lower educational level and social isolation were associated with self-reported vision problems with ORs of 2.66 [2.42-2.92], 2.16 [2.01-2.32], 1.11 [1.01-1.23], 1.31 [1.21-1.42], 1.29 [1.19-1.40] and 1.45 [1.26-1.67], respectively, while higher income was associated with less self-reported vision problems with OR of 0.80 [0.73-0.86]. CONCLUSIONS: This study demonstrated inequalities in terms of prevalence of self-reported vision problems in Europe, with higher prevalence in Eastern European countries and among women and older individuals

Novel structural parameters of Ig -Ag complexes yield a quantitative description of interaction specificity and binding affinity

Antibody-antigen complexes challenge our understanding, as analyses to datefailed to unveil the key determinants of binding affinity and interaction specificity. We par-tially fill this gap based on novel quantitative analyses using two standardized databases, theIMGT/3Dstructure-DB and the structure affinity benchmark.First, we introduce a statistical analysis of interfaces which enables the classification of ligand types(protein, peptide, chemical; cross-validated classification error of 9.6%), and yield binding affinitypredictions of unprecedented accuracy (median absolute error of 0.878 kcal/mol). Second, weexploit the contributions made by CDRs in terms of position at the interface and atomic packingproperties to show that in general, VH CDR3 and VL CDR3 make dominant contributions tothe binding affinity, a fact also shown to be consistent with the enthalpy - entropy compensationassociated with pre-configuration of CDR3.Our work suggests that the affinity prediction problem could be solved from databases of highresolution crystal structures of complexes with known affinity

Modeling the antibody response : from the structure of immunoglobulins - antigen complexes to the clonal complexity of heavy chain repertoires

Cette thèse étudie trois sujets relevant de la biologie structurale, de lagénétique et de l'immunologie.Premièrement, nous développons de nouveaux prédicteurs de l'affinité deliaison de complexes protéiques, produisant des résultats de niveau ``état del'art''. Nous calculons d'abord 12 variables modélisant diverses propriétésstructurales des complexes. Nous générons et évaluons des estimateursutilisant des sous ensembles de ces variables, de façon à identifier les plusperformants. Le logiciel associé est distribué dans la Structural BioinformaticsLibrary.Deuxièmement, nous proposons de nouvelles analyses de complexes Ig-Ag.D'une part nous concevons un classificateur distinguant les types de ligand desIg. D'autre part, nous montrons que le modèle précédent prédit fidèlementl'affinité de complexes Ig-Ag. Enfin, nous quantifions la contribution des CDR3de la chaine lourde à l'affinité de liaison, et montrons qu'il contribuesignificativement plus que les autres CDR.Enfin, nous nous intéressons à la modélisation de la diversité des répertoiresde chaîne lourde des Igs, à partir de données de séquençage de CDR3, dans unmodèle de vaccin chez le poisson. Nous analysons les répertoires dans troisconditions: naifs, vaccinés et vaccinés + infectés. Nous comparons lesrépertoires de deux individus en utilisant la « earth-mover distance », laquelleexploite la correspondance entre clonotypes de deux répertoires, révélant ainsides informations inaccessibles aux méthodes basées sur les indices dediversité.Dépôt de thèseDonnées complémentairesPour caractériser la notion de réponse immunitaire publique / privée, nousquantifions le chevauchement des clonotypes exprimés entre individus de lamême ou de différentes conditionsThis thesis investigates three topics at the cross-roads of structural biology,genetics and immunology.First, we develop a pipeline to design and select binding affinity predictors forprotein complexes, yielding state-of-the art results. The first step is the designand computation of 12 different variables accounting for geometric andphysico-chemical properties of the complexes. The second step is thegeneration and evaluation of models using subsets of these variables, followedby the selection of the best performing ones. The corresponding software isdistributed within the Structural Bioinformatics Library.Second, we provide an analysis of the interface properties of Ig-Ag complexes.In particular, we design a classifier using two descriptors, which is able todistinguish ligand types. We also apply the previous binding affinity predictionmodel to Ig-Ag complexes and obtain accurate predictions. We then develop aquantitative model for the contribution of VH CDR3 to the binding affinity andinteraction specificity, and show that it contributes significantly more thanother CDRs.Third, we model the diversity of VH CDR3 repertoires from Ig RNA sequencingdata in a fish vaccination model. We analyze repertoires from three conditions:naive, vaccinated and vaccinated + infected fish. Comparison of the repertoiresof two individuals uses the earth-mover distance (EMD). By exploiting amapping between the clonotypes of the repertoires, we show that EMD revealsinformation beyond classical methods based on diversity indexes. Tocharacterize the notion of public / private immune response, we quantify theoverlap of clonotypes between individuals of the same or different condition