Protein folding pathways extracted by OFLOOD: Outlier flooding method

Abstract

The Outlier FLOODing method (OFLOOD) is proposed as an efficient conformational sampling method to extract biologically rare events such as protein folding. In OFLOOD, sparse distributions (outliers in the conformational space) were regarded as relevant states for the transitions. Then, the transitions were enhanced through conformational resampling from the outliers. This evidence indicates that the conformational resampling of the sparse distributions might increase chances for promoting the transitions from the outliers to other meta-stable states, which resembles a conformational flooding from the outliers to the neighboring clusters. OFLOOD consists of (i) detections of outliers from conformational distributions and (ii) conformational resampling from the outliers by molecular dynamics (MD) simulations. Cycles of (i) and (ii) are simply repeated. As demonstrations, OFLOOD was applied to folding of Chignolin and HP35. In both cases, OFLOOD automatically extracted folding pathways from unfolded structures with ns-order computational costs, although ms-order canonical MD failed to extract them.