The energy landscape that organizes microstates of a molecular system and governs theunderlying molecular dynamics exposes the relationship between molecular form/structure, changesto form, and biological activity or function in the cell. However, several challenges stand in the wayof leveraging energy landscapes for relating structure and structural dynamics to function. Energylandscapes are high-dimensional, multi-modal, and often overly-rugged. Deep wells or basins inthem do not always correspond to stable structural states but are instead the result of inherentinaccuracies in semi-empirical molecular energy functions. Due to these challenges, energeticsis typically ignored in computational approaches addressing long-standing central questions incomputational biology, such as protein decoy selection. In the latter, the goal is to determine over apossibly large number of computationally-generated three-dimensional structures of a protein thosestructures that are biologically-active/native. In recent work, we have recast our attention on theprotein energy landscape and its role in helping us to advance decoy selection. Here, we summarizesome of our successes so far in this direction via unsupervised learning. More importantly, we furtheradvance the argument that the energy landscape holds valuable information to aid and advance thestate of protein decoy selection via novel machine learning methodologies that leverage supervisedlearning. Our focus in this article is on decoy selection for the purpose of a rigorous, quantitativeevaluation of how leveraging protein energy landscapes advances an important problem in proteinmodeling. However, the ideas and concepts presented here are generally useful to make discoveriesin studies aiming to relate molecular structure and structural dynamics to function.
Keywords: basin; decoy selection; energy landscape; machine learning; model quality assessment; purity.