A hybrid model combining evolutionary probability and machine learning leverages data-driven protein engineering

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Protein engineering through directed evolution and (semi-)rational approaches has been applied successfully to optimize protein properties for broad applications in molecular biology, biotechnology, and biomedicine. The potential of protein engineering is not yet fully realized due to the limited screening throughput hampering the efficient exploration of the vast protein sequence space. Data-driven strategies have emerged as a powerful tool to leverage protein engineering by providing a model of the sequence-fitness landscape that can exhaustively be explored in silico and capitalize on the high diversity potential offered by nature However, as both the quality and quantity of the inputted data determine the success of such approaches, the applicability of data-driven strategies is often limited due to sparse data. Here, we present a hybrid model that combines direct coupling analysis and machine learning techniques to enable data-driven protein engineering when only few labeled sequences are available. Our method achieves high performance in predicting a protein’s fitness based on its sequence regardless of the number of sequences-fitness pairs in the training dataset. Besides reducing the computational effort compared to state-of-the-art methods, it outperforms them for sparse data situations, i.e., 50 − 250 labeled sequences available for training. In essence, the developed method is auspicious for data-driven protein engineering, especially for protein engineers who have only access to a limited amount of data for sequence-fitness landscape modeling.

Authors 4

1. Alexander-Maurice Illig Aachen Institute of Biotechnology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biotechnology, RWTH Aachen University, Worringerweg 3, Aachen, 52074, North Rhine-Westphalia, Germany

   Institute of Biotechnology, RWTH Aachen University

2. Niklas E. Siedhoff Aachen Institute of Biotechnology

   RWTH Aachen University

   Affiliation as printed

   Institute of Biotechnology, RWTH Aachen University, Worringerweg 3, Aachen, 52074, North Rhine-Westphalia, Germany

   Institute of Biotechnology, RWTH Aachen University

3. Ulrich Schwaneberg Aachen DWI - Leibniz Institute for Interactive Materials Institute of Biotechnology

   DWI – Leibniz Institute for Interactive Materials · RWTH Aachen University

   Affiliation as printed

   DWI-Leibniz Institute for Interactive Materials, Forckenbeckstraße 50, Aachen, 52074, North Rhine-Westphalia, Germany

   Institute of Biotechnology, RWTH Aachen University, Worringerweg 3, Aachen, 52074, North Rhine-Westphalia, Germany

   DWI-Leibniz Institute for Interactive Materials, Forckenbeckstraße 50, Aachen, 5074, North Rhine-Westphalia, Germany

   Institute of Biotechnology, RWTH Aachen University

4. Mehdi D. Davari corresponding

   Leibniz Institute of Plant Biochemistry

   Affiliation as printed

   Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, Halle, 06120, Saxony-Anhalt, Germany

   Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg , Halle, 06120, Saxony-Anhalt, Germany