Abstract
Protein–protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein–protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein–protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein–protein interface.
Highlights
Protein–protein interactions (PPIs) lie at the heart of the machinery of life
Even if the interacting partners are considered to be rigid, i.e., when the conformational changes induced by the binding process lead to a root mean square deviation (RMSD) that is below 1 Å, the protein interface remains a dynamic object, and trajectories from short (50 ns) molecular dynamics (MD) simulations can be used to study the effect of the solvent on the complex surface
The dynasome, the ensemble of mobility can be presented by a proa protein, has been i.e., considered a central elementpatterns in our that understanding of proteins for tein, has been considered a central element in our understanding of proteins for a over a decade, as it was often described as the missing link between structure andover funcdecade, as it was often described as the missing link between structure and function tion [167]
Summary
Protein–protein interactions (PPIs) lie at the heart of the machinery of life. Numerous cell mechanisms, such as metabolic pathways, transport or immune response, rely heavily on protein interaction networks [1–3]. Established in 2001, the CAPRI (Critical Assessment of predicted Inone attempts to determine the structure of a protein complex starting from its individual teractions) initiative has developments in docking and scoring methpartners. Predictedboth hastertiary introduced an nary structure prediction [26–28] Both CAPRI and CASP, the standard assessassembly category in ordermethods to combine bothInworlds, i.e., tertiary and quaternary structure ment criteria used to validate protein complex models rely on a single reference. In both CAPRI and CASP, the standard assessment criteria structure of the target complex. This view endorses the image of a static protein–protein used to validate protein complex models rely on a single reference X-ray structure of the interface, which This has been years.
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