Studies in the assessment of folding quality for protein modeling and structure prediction

A diagnostic for assessing the quality of a fold has been developed to which further criteria can be progressively added. The goal is to create a measure that can follow the status of a protein structure in a simulation or modeling process, when the answer (the experimental structure) is not known in advance, rather than simply reject deliberate misfolds. This places greater emphasis on the need to study, and calibrate against, marginal cases, i.e., unusual native structures, incomplete structures, partially erroneous X-ray structures, good models, poor models, and the effect of cofactors. The first three terms introduced in the diagnostic are appropriate core-forming properties or noncore properties of residues in relation to tertiary structure, appropriate neighboring structure density for each residue in relation to tertiary structure, and secondary structure consistency. While the method emerges as a useful simulation analysis tool, we find a need for further fine-tuning to diminish sensitivity to minor conformational changes that retain essential features of the fold, balanced against the need to obtain a more sensitive response when a conformational change involves less physically meaningful interatomic interactions. This dual utility is difficult to obtain: the investigation highlights some of the issues. Initial attempts to obtain it have led to terms in the diagnostic that are admittedly complex: simplifications must also be explored.