Energy design for protein-protein interactions.
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ABSTRACT:
SUBMITTER: Ravikant DV
PROVIDER: S-EPMC3170394 | biostudies-other | 2011 Aug
REPOSITORIES: biostudies-other
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Project description:A detailed error analysis is presented for the computation of protein-ligand interaction energies. In particular, we show that it is probable that even highly accurate computed binding free energies have errors that represent a large percentage of the target free energies of binding. This is due to the observation that the error for computed energies quasi-linearly increases with the increasing number of interactions present in a protein-ligand complex. This principle is expected to hold true for any system that involves an ever increasing number of inter or intra-molecular interactions (e.g. ab initio protein folding). We introduce the concept of best-case scenario errors (BCS(errors)) that can be routinely applied to docking and scoring exercises and used to provide errors bars for the computed binding free energies. These BCS(errors) form a basis by which one can evaluate the outcome of a docking and scoring exercise. Moreover, the resultant error analysis enables the formation of an hypothesis that defines the best direction to proceed in order to improve scoring functions used in molecular docking studies.
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Project description:Understanding protein folding is crucial for protein sciences. The conformational spaces and energy landscapes of cold (unfolded) protein states, as well as the associated transitions, are hardly explored. Furthermore, it is not known how structure relates to the cooperativity of cold transitions, if cold and heat unfolded states are thermodynamically similar, and if cold states play important roles for protein function. We created the cold unfolding 4-helix bundle DCUB1 with a de novo designed bipartite hydrophilic/hydrophobic core featuring a hydrogen bond network which extends across the bundle in order to study the relative importance of hydrophobic versus hydrophilic protein-water interactions for cold unfolding. Structural and thermodynamic characterization resulted in the discovery of a complex energy landscape for cold transitions, while the heat unfolded state is a random coil. Below ∼0 °C, the core of DCUB1 disintegrates in a largely cooperative manner, while a near-native helical content is retained. The resulting cold core-unfolded state is compact and features extensive internal dynamics. Below -5 °C, two additional cold transitions are seen, that is, (i) the formation of a water-mediated, compact, and highly dynamic dimer, and (ii) the onset of cold helix unfolding decoupled from cold core unfolding. Our results suggest that cold unfolding is initiated by the intrusion of water into the hydrophilic core network and that cooperativity can be tuned by varying the number of core hydrogen bond networks. Protein design has proven to be invaluable to explore the energy landscapes of cold states and to robustly test related theories.
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