Improving the Reliability of Protein Folding Rate Predictions by Applying Guidelines for Validating QSAR/QSPR Models

Quantitative structure–activity/property relationship (QSAR/QSPR) is a well-established methodology widely used to model molecular properties based on structure, and is applied in fields such as drug design and environmental protection. The knowledge and procedures developed and used in QSPR modelling will be applied to the validation of protein folding rate models. Understanding the protein folding process is considered one of the most important scientific topics, and identifying the fundamental factors responsible for protein folding has been the subject of intensive research over the past 30 years [1]. Among the structural descriptors determining the protein folding rate, the length of the protein sequence, the content of regular secondary structures, and the average contact row distance between amino acids in the 3D structure are the most important. Comparative studies of different methods for predicting protein folding rates are occasionally published, and we conducted one such study. We found that the experimental data in literature databases and the data available online are inconsistent and scattered. This is partly due to differences in experimental data and protein sequence lengths, but more so due to the questionable quality of the models themselves. We observed very large deviations in the predictions of ln(kf) by some of the analysed models implemented as web servers. The root mean square errors (RMSEs) of some of the analysed models in predicting ln(kf) for a new external set of proteins are much larger than the RMSEs obtained for the same models on the training sets. External validation demonstrates that protein folding rate models available on web servers have accuracy for external protein sets comparable to that of a simple model based solely on the logarithm of protein chain length. This finding, which highlights the importance of external model validation as recommended by the OECD guidelines for QSAR validation, is fundamental and offers a new perspective for improving protein folding rate models by applying the knowledge and procedures used in the QSPR methodology.