Résumé
Oligomeric proteins, comprising two or more associating polypeptide chains, represent a large fraction of cellular proteins. In particular, many proteins self-associate into homooligomers to gain functional advantages. Our understanding of the oligomerization at the molecular level is currently limited because intermediates that occur in the process are short-lived in most occasions, precluding a direct experimental characterization. Using molecular dynamics simulations, enhanced by a sampling method developed in our group, we obtained an atomistic description of the assembly of an evolutionary-optimized trimeric protein. Our results are in excellent agreement with available experimental data and extend the current view of oligomerization by showing the importance of the apparently contradictory requirements of monomer preorganization and conformational flexibility. In the realm of protein–protein interactions, the assembly process of homooligomers plays a fundamental role because the majority of proteins fall into this category. A comprehensive understanding of this multistep process requires the characterization of the driving molecular interactions and the transient intermediate species. The latter are often short-lived and thus remain elusive to most experimental investigations. Molecular simulations provide a unique tool to shed light onto these complex processes complementing experimental data. Here we combine advanced sampling techniques, such as metadynamics and parallel tempering, to characterize the oligomerization landscape of fibritin foldon domain. This system is an evolutionarily optimized trimerization motif that represents an ideal model for experimental and computational mechanistic studies. Our results are fully consistent with previous experimental nuclear magnetic resonance and kinetic data, but they provide a unique insight into fibritin foldon assembly. In particular, our simulations unveil the role of nonspecific interactions and suggest that an interplay between thermodynamic bias toward native structure and residual conformational disorder may provide a kinetic advantage.