Moving pictures: Reassessing docking experiments with a dynamic view of protein interfaces

Abstract

The modeling of protein assemblies at the atomic level remains a central issue in structural biology, as protein interactions play a key role in numerous cellular processes. This problem is traditionally addressed using docking tools, where the quality of the models is based on their similarity to a single reference experimental structure. However, using a static reference does not take into account the dynamic quality of the protein interface. Here, we used all‐atom classical Molecular Dynamics simulations to investigate the stability of the reference interface for three complexes that previously served as targets in the CAPRI competition. For each one of these targets, we also ran MD simulations for ten models that are distributed over the High, Medium and Acceptable accuracy categories. To assess the quality of these models from a dynamic perspective, we set up new criteria which take into account the stability of the reference experimental protein interface. We show that, when the protein interfaces are allowed to evolve along time, the original ranking based on the static CAPRI criteria no longer holds as over 50% of the docking models undergo a category change (which can be either toward a better or a lower accuracy group) when reassessing their quality using dynamic information.

A dynamical view of protein-protein complexes: Studies by molecular dynamics simulations

“…Let us recall here that we simulated only complexes that behave as rigid bodies, so rigid bodies do not equal static objects. As observed in recent works ( Jandova et al, 2021 ; Prévost and Sacquin-Mora, 2021 ), the protein-protein complexes visited conformations outside the high quality range of CAPRI, suggesting that docking model evaluation should take this variability into account.…”

“…They observed higher stability of interface properties for native models, and also noticed significant changes in simulations starting from crystallographic structures in their simulations of 100 ns. In another recent work, Prévost and Sacquin-Mora performed MD simulations on docking models of various quality for three complexes submitted at the CAPRI competition and observed a category change (in terms of model quality) for more than half of the models ( Prévost and Sacquin-Mora, 2021 ). Crystallographic structures stayed in the medium quality range in their 100 ns simulations and preserved more than 50% of their native contacts.…”

“…Concerning the interfaces, Shaw and co-workers performed hundred-microsecond MD simulations of the protein-protein association in five complexes which allowed observing transition states before native association, with low fraction of native contacts and highly hydrated interfaces ( Pan et al, 2019 ). Two recent studies of models obtained by protein-protein docking have shown that their interfaces undergo significant changes in simulations, and also observed changes in the interfaces of native complexes ( Jandova et al, 2021 ; Prévost and Sacquin-Mora, 2021 ). Similar findings were also obtained by us for protein-DNA complexes.…”

Building Biological Relevance Into Integrative Modelling of Macromolecular Assemblies

“…At the same time, the interface loses up to 50% of its initial residue pair contacts, stabilizing to a new network of residue-residue contacts that is 86% conserved on average during the last 225 ns of the simulation ( Figure 5B , insert). Recent studies, both on RecA filaments and on heterodimers, showed that stable interfaces typically conserve 70–90% of their interaction contact network when simulated at 300 K, due to thermal movements ( Boyer et al, 2019 ; Prévost and Sacquin-Mora, 2021 ).…”

Modeling the Dynamics of Protein–Protein Interfaces, How and Why?

“…Again, native models show higher stability in almost all measured properties, including the criteria traditionally used for scoring complex models in CAPRI, namely the ligand and interface RMSDs, and the fraction of native contacts from the reference experimental structure of the protein complex. Prévost and Sacquin-Mora also questioned the relevance of the current CAPRI criteria, as they are based on a single static reference structure [ 140 ]. In their work, they ran MD simulations both on the experimental reference structure and various near-native models for three CAPRI targets (see, for example, T29 in Figure 2 a) and showed how using dynamic criteria (based on the trajectory analysis and not on a single structure) can impact the models’ ranking, as they display different stabilities over time.…”