What makes it difficult to refine protein models further via molecular dynamics simulations?

Protein structure refinement remains a challenging yet important problem as it has the potential to bring already accurate template‐based models to near‐native resolution. Refinement based on molecular dynamics simulations has been a highly promising approach and the performance of MD‐based refinement in the Feig group during CASP12 is described here. During CASP12, sampling was extended well into the microsecond scale, an improved force field was applied, and new protocol variations were tested. Progress over previous rounds of CASP was found to be limited which is analyzed in terms of the quality of the initial models and dependency on the amount of sampling and refinement protocol variations. As current MD‐based refinement protocols appear to be reaching a plateau, detailed analysis is presented to provide new insight into the major challenges towards more extensive structure refinement, focusing in particular on sampling with and without restraints.

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