Evolutionary search strategies for efficient sample-based representations of multiple-basin protein energy landscapes

Protein function is the result of a complex yet precise relationship between protein structure and dynamics. The ability of a protein to assume different structural states is key to biomolecular recognition and function modulation. Protein modeling research is driven by the need to complement experimental techniques in obtaining a comprehensive and detailed characterization of protein equilibrium dynamics. This is a non-trivial task, as it requires mapping the structure space (and underlying energy landscape) available to a protein under physiological conditions. Existing algorithms invariably adopt a stochastic optimization approach to explore the non-linear and multimodal protein energy landscapes. At the present, such algorithms suffer from limited sampling, particularly in high-dimensional and non-linear variable spaces rich in local minima. In this paper, we equip a recently published evolutionary algorithm with novel evolutionary search strategies to enhance the sampling capability for mapping multi-basin protein energy landscapes. We investigate initialization strategies to delay premature convergence and techniques to maintain and update on-the-fly a sample-based representation that serves as a map of the energy landscape. Applications on three proteins central to human disease show that the novel strategies are effective at locating basins in complex energy landscapes with a practical computational budget.