Abstract
Small-angle X-ray scattering (SAXS) experiments provide low-resolution but valuable information about the dynamics of biomolecular systems, which could be ideally integrated into molecular dynamics (MD) simulations to accurately determine conformational ensembles of flexible proteins. The applicability of this strategy is hampered by the high computational cost required to calculate scattering intensities from three-dimensional structures. We previously presented a hybrid resolution method that makes atomistic SAXS-restrained MD simulation feasible by adopting a coarse-grained approach to efficiently back-calculate scattering intensities; here, we extend this technique, applying it in the framework of metainference with the aim to investigate the dynamical behavior of flexible biomolecules. The efficacy of the method is assessed on the K63-diubiquitin, showing that the inclusion of SAXS restraints is effective in generating a reliable conformational ensemble, improving the agreement with independent experimental data.
Highlights
Biomolecules in solution can be characterized by a different extent of conformational dynamics, depending on the specific system and experimental conditions.[1−3] While the dynamics of single-domain proteins under native conditions is generally limited to fluctuations around a well-defined structure, fully disordered proteins can only be described as statistical ensembles of conformations
The use of the hybrid approach significantly improved the performances of small-angle Xray scattering (SAXS)-driven molecular dynamics (MD) simulations, compared to the ones adopting atomistic scattering evaluation
We have presented a hybrid-resolution MD-based strategy, which is useful with regard to determining conformational ensembles that provide an accurate interpretation of SAXS data
Summary
Biomolecules in solution can be characterized by a different extent of conformational dynamics, depending on the specific system and experimental conditions.[1−3] While the dynamics of single-domain proteins under native conditions is generally limited to fluctuations around a well-defined structure, fully disordered proteins can only be described as statistical ensembles of conformations. Between these cases, multidomain proteins connected by linker regions can populate multiple states generally characterized by a different size.[4]. An atomistic interpretation of scattering data could benefit from its combination with computational techniques, such as molecular dynamics (MD) simulations, which could provide an accurate physical model to generate reliable conformational ensembles, in agreement with SAXS data.[6,7] Common approaches employ SAXS to reweight conformational ensembles a posteriori, making use of statistically founded theoretical frameworks.[8−14] Recently, few methods in which SAXS experimental data are integrated into MD to drive conformational sampling have been proposed; their application is hindered by the high computational cost required to calculate scattering intensities.[15−18]
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