Interfacial dynamics and growth modes ofβ₂-microglobulin dimers

Abstract

Protein aggregation is a complex process that strongly depends on environmental conditions and has considerable structural heterogeneity, not only at the level of fibril structure but also at the level of molecular oligomerization. Since the first step in aggregation is the formation of a dimer, it is important to clarify how certain properties (e.g., stability or the interface geometry) of the latter may determine the outcome of aggregation. Here, we developed a simple model that represents the dimer's interfacial region by two angles (spanning the so-called growth landscape), and investigate how modulations of the interfacial region occurring on the ns - μs timescale change the dimer's growth mode. We applied this methodology to 15 different dimer configurations of the β2m D76N mutant protein equilibrated with long MD simulations and identified which of them have limited and unlimited growth modes, with different consequences to their aggregation potential. We found that despite the highly dynamic nature of the starting configurations, most polymeric growth modes tend to be conserved within the studied time scale. The proposed methodology performs remarkably well taking into consideration that the β2m dimers are formed by monomers with detached termini, and their interfaces are stabilized by non-specific apolar interactions, leading to relatively weak binding affinities.

Is There a Functional Role for the Knotted Topology in Protein UCH-L1?

“…To evaluate the binding free energies of the considered ubiquitin-complex systems, we performed Molecular Mechanics-Poisson−Boltzmann/Surface Area (MM-PBSA) calculations. These calculations were performed using pyBindE, 61,62 which is a Python-based software specifically designed for conducting MM-PBSA calculations with GROMOS54A7 force field parameters.…”