Section: New Results

Modeling Interfaces and Contacts

Keywords: docking, scoring, interfaces, protein complexes, Voronoi diagrams, arrangements of balls.

High Resolution Crystal Structures Leverage Protein Binding Affinity Predictions

Participants : Frédéric Cazals, Simon Marillet.

In collaboration with P. Boudinot, Unité de recherche en virologie et immunologie moléculaires, INRA Jouy-en-Josas.

Predicting protein binding affinities from structural data has remained elusive, a difficulty 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 former route unnecessarily restricts the model space, while the latter is prone to overfitting.

We design models in a third tier [20] , using twelve variables describing enthalpic and entropic variations upon binding, and a model selection procedure identifying the best sparse model built from a subset of these variables. Using these models, we report three main results. First, we present models yielding a marked improvement of affinity predictions. For the whole dataset, we present a model predicting $K_d$ 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 high resolution structures. Second, we show that these performances owe to a new parameter encoding interface morphology and packing properties of interface atoms. Third, we argue that interface flexibility and prediction hardness do not correlate, and that for flexible cases, a performance matching that of the whole SAB can be achieved. Overall, our work suggests that the affinity prediction problem could be partly solved using databases of high resolution complexes whose affinity is known.

Dissecting Interfaces of Antibody - Antigen Complexes: from Ligand Specific Features to Binding Affinity Predictions

Participants : Frédéric Cazals, Simon Marillet.

In collaboration with: P. Boudinot, Unité de recherche en virologie et immunologie moléculaires, INRA Jouy-en-Josas; M-P. Lefranc, Univ. of Montpellier 2.

B lymphocytes recognize the antigen through their membrane immunoglobulins (IG), that can also be secreted. The diversity of IG-Ag complexes challenges our understanding in terms of binding affinity and interaction specificity.

In this work [21] , we dissect the interfaces of IG-Ag complexes from high resolution crystal structures. We show that global interface statistics distinguish ligand types and that interfacial side chains play a key role in the interaction. Our analysis of the relative positions of CDR identifies a remarkably conserved pattern involving seven seams between CDR, with specific variations depending on the ligand type. Finally, we show that structural features of the interface and of the partners yield binding affinity estimates of unprecedented accuracy (median absolute error of 1.02 kcal/mol).

Our findings will be of broad interest, as understanding Ag recognition at the atomic level will help guiding design of better IG targeting Ag for therapeutic or other uses.