Abstract
We used the PACSAB protein model, based on the implicit solvation approach, to simulate protein–protein recognition and study the effect of helical structure on the association of aggregating peptides. After optimization, the PACSAB force field was able to reproduce correctly both the correct binding interface in ubiquitin dimerization and the conformational ensemble of the disordered protein activator for hormone and retinoid receptor (ACTR). The PACSAB model allowed us to predict the native binding of ACTR with its binding partner, reproducing the refolding upon binding mechanism of the disordered protein.
Highlights
The exponential increase in computational power along with the use of parallelized algorithms for molecular dynamics (MD) simulations has made it possible to reach computational timescales beyond the microsecond, where processes like protein association/dissociation or the full conformational sampling of disordered proteins occur
We found that the PACSAB parametrization that gives better results for the ubiquitin solution better approaches the experimental radius of gyration than explicit solvent simulations with TIP4P/2005 water, the radius of gyration distribution obtained for this parametrization of the force field is still below the value estimated from experiments
We found in this work that PACSAB, a coarse-grained protein model based on the implicit solvent approach, is able to predict the correct binding interface in the binding of both a stable protein and a disordered protein (ACTR), improving the results of explicit solvent atomistic simulations for these systems
Summary
The exponential increase in computational power along with the use of parallelized algorithms for molecular dynamics (MD) simulations has made it possible to reach computational timescales beyond the microsecond, where processes like protein association/dissociation or the full conformational sampling of disordered proteins occur. Several works [1,2,3] have shown that current water models and force fields tend to produce binding interfaces between two protein molecules that are known from experiment to be wrong [4] (nonspecific association), overestimating association and producing a fraction of monomers much lower than the real, experimentally measured value. This spurious tendency protein association has been related to the general tendency to produce overly collapsed structural ensembles for disordered proteins [5]. A system of two Aβ molecules with a concentration of 30 μM involves the use of a simulation box size of 48 nm, which contains around
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