Selection Rules for Outliers in Outlier Flooding Method Regulate Its Conformational Sampling Efficiency.

The outlier flooding method (OFLOOD) has been proposed as an enhanced conformational sampling method of proteins. In OFLOOD, rarely occurring states of proteins are detected as sparse conformational distributions (outliers) with a clustering algorithm. The detected outliers are intensively resampled with short-time molecular dynamics (MD) simulations. As a set of cycles, OFLOOD repeats selections of outliers and their conformational resampling. Herein, as an essential issue to be tackled to perform OFLOOD efficiently, a selection rule for outliers should be carefully specified. Generally, many outliers are detected from distributions on conformational subspaces with the clustering. Judging from its computational costs, it is unreasonable to select all the detected outliers upon the conformational resampling. Therefore, it is important to consider which outliers should be selected from the sparse distributions when restarting their short-time MD simulations with limited computational costs. In this sense, we investigated the conformational sampling efficiency of OFLOOD by changing the selection rules for outliers. To address the conformational sampling efficiency of OFLOOD depending on its selection rules, outliers to be resampled were selected by focusing their probability occurrences (populations of outliers). As a comparison, a random selection rule for outliers was also considered. Through the present assessment, the random selection of outliers showed the most efficient conformational sampling efficiency compared to the other OFLOOD trials using the biased selection rules, indicating that a variety of outliers should be selected and resampled during the OFLOOD cycles. In conclusion, the random outlier selection rule is the best strategy to perform OFLOOD efficiently.