A critical assessment of hidden markov model sub-optimal sampling strategies applied to the generation of peptide 3D models

Hidden Markov Model derived structural alphabets are a probabilistic framework in which the complete conformational space of a peptidic chain is described in terms of probability distributions that can be sampled to identify conformations of largest probabilities. Here, we assess how three strategies to sample sub-optimal conformations-Viterbi k-best, forward backtrack and a taboo sampling approach-can lead to the efficient generation of peptide conformations. We show that the diversity of sampling is essential to compensate biases introduced in the estimates of the probabilities, and we find that only the forward backtrack and a taboo sampling strategies can efficiently generate native or near-native models. Finally, we also find such approaches are as efficient as former protocols, while being one order of magnitude faster, opening the door to the large scale de novo modeling of peptides and mini-proteins. © 2016 Wiley Periodicals, Inc.