Dead-End Elimination with a Polarizable Force Field Repacks PCNA Structures

A balance of van der Waals, electrostatic, and hydrophobic forces drive the folding and packing of protein side chains. Although such interactions between residues are often approximated as being pairwise additive, in reality, higher-order many-body contributions that depend on environment drive hydrophobic collapse and cooperative electrostatics. Beginning from dead-end elimination, we derive the first algorithm, to our knowledge, capable of deterministic global repacking of side chains compatible with many-body energy functions. The approach is applied to seven PCNA x-ray crystallographic data sets with resolutions 2.5-3.8 Å (mean 3.0 Å) using an open-source software. While PDB_REDO models average an Rfree value of 29.5% and MOLPROBITY score of 2.71 Å (77th percentile), dead-end elimination with the polarizable AMOEBA force field lowered Rfree by 2.8-26.7% and improved mean MOLPROBITY score to atomic resolution at 1.25 Å (100th percentile). For structural biology applications that depend on side-chain repacking, including x-ray refinement, homology modeling, and protein design, the accuracy limitations of pairwise additivity can now be eliminated via polarizable or quantum mechanical potentials.