Effects of frustration, confinement, and surface interactions on the dimerization of an off-lattice β-barrel protein

Abstract

We study the effects of confinement, sequence frustration, and surface interactions on the thermodynamics of dimerization of an off-lattice minimalist beta-barrel protein using replica exchange molecular dynamics. We vary the degree of frustration of the protein by tuning the specificity of the hydrophobic interactions and investigate dimerization in confining spheres of different radii. We also investigate surface effects by tethering the first residue of one of the proteins to a uniformly repulsive surface. We find that increasing the confinement and frustration stabilize the dimer, while adding a repulsive surface decreases its stability. Different ensembles of structures, including properly dimerized and various partially dimerized states, are observed at the association transition temperature T(a), depending on the amount of frustration and whether a surface is present. The presence of a surface is predicted to alter the morphology of larger aggregates formed from partially unfolded dimeric conformations.

Insights from Coarse-Grained Gō Models for Protein Folding and Dynamics

“…Symmetrized Gō potentials have been employed for domain swapping and amyloid aggregation in which intermonomer residue contacts are treated identical to intramonomer native contacts [ 13 , 14 , 154 ]. Gō model simulations have been performed to explore the influence of macromolecular crowding agents [ 155 , 156 ] and confinement [ 62 ] on folding. Electrostatic interactions were incorporated between a Gō model of a transcription factor and coarse-grained DNA, which caused the protein to visit partially unfolded forms and suggested a fly casting mechanism of target recognition [ 157 ].…”

“…Qualitative consensus is generally obtained between predictions and experiment for individual residue phi-values as well as the major features of the folding mechanism and folding rate [ 55 ]. Non-native interactions have been demonstrated to make some important contributions to the folding transition state and mechanism, and variants of the Gō algorithm have been modified to incorporate nonspecific interactions [ 4 , 10 , 13 , 56 – 62 ]. Notwithstanding, the widespread success of native-only Gō models in reproducing folding behavior as observed in experiment and atomistic simulation [ 63 ] suggests that the perturbations of non-native interactions on the structures of folding transition states and intermediates are minor in comparison to the dominating influence of native interactions on the funneled energy landscape [ 64 ].…”

The Physics of the Interactions Governing Folding and Association of Proteins

“…82 Computer simulations have also shown that native state stability, refolding rates, and self-assembly of model proteins are enhanced by crowding and confinement. [83][84][85][86] All these results highlight the significance of investigating protein function and stability in environments mimicking in vivo conditions to uncover structural and dynamic properties that may not be captured in dilute solution.…”

Reaching new levels of realism in modeling biological macromolecules in cellular environments

“…Additional terms may be used to modulate attractive or repulsive interactions [153, 156, 157], add electrostatic interactions via a Debye-Hückel potential [155, 159], or add certain residue-residue interactions with Go-like potentials to favor specific native-like folds of proteins that could otherwise not be maintained [152, 154]. Some of these studies aim at modeling specific proteins or peptides, while other models describe polymers with general protein-like properties through a combination of hydrophilic and hydrophobic beads [31, 151, 157, 158, 161–163]. Slightly more detailed models include two beads per residue, one at the Cα position and another one representing the amino acid side chain [29, 164–174].…”