Protein folding in the hydrophobic-hydrophilic (HP) is NP-complete
RECOMB '98 Proceedings of the second annual international conference on Computational molecular biology
Introduction to Algorithms
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Protein folding is a long standing problem in biology, whose mechanism is still not completely understood. Funnel-shape energy landscape has been proposed as a plausible folding mechanism in which proteins can fold through multiple possible pathways from unfolded states to their specific three dimensional structures. However, the factors that determine the funnel-shape energy landscapes are largely unknown. In this study, we use the hydrophobic-hydrophilic (HP) model, a simplified model for studying protein folding, to investigate the factors that affect the shapes of protein energy landscapes. We designed a clustering method based on graph theory to analyze the conformations sampled using a recently developed Monte Carlo method, FRESS. We found that the way protein motions are modeled (the move sets) has a significant effect on the shape of protein energy landscapes. We also found that sequences with around 40--50% hydrophobic residues tend to have a stable state represented by a single dominant cluster, consisting of a large number of similar conformations. The energy landscapes resemble a funnel, where there are many paths to minimum energy conformations in the dominant cluster from conformations of higher energies. We also found that sequences with hydrophobic residues above or below the optimal range of 40--50% do not have a single stable state. Instead, there are numerous small clusters, representing multiple local energy minima. Our finding is consistent with the compositions of hydrophobic and polar residues in globular proteins (which fold to unique structures), where on average there are around 45% hydrophobic residues in globular proteins. Our study suggests that hydrophobic interaction is likely a major force leading to the funnel-shape energy landscape of proteins; and the composition of hydrophobic and polar residues is an important sequence feature for the formation of funnel-shape of protein energy landscapes.