H. Kamisetty, A. Ramanathan, C. Bailey-Kellogg, and C.J. Langmead, "Accounting for conformational entropy in predicting binding free energies of protein-protein interactions", Proteins, 2011, 79:444-462. [paper]

Protein-protein interactions are governed by the change in free energy upon binding, ΔΔ Gbind=Δ H - T Δ S. These interactions are often marginally stable, so one must examine the balance between the change in enthalpy, Δ H, and the change in entropy, Δ S, when investigating known complexes, characterizing the effects of mutations, or designing optimized variants. In order to perform a large-scale study into the contribution of conformational entropy to binding free energy, we developed a technique called Goblin (Graphical mOdel for BiomoLecular INteractions) that performs physics-based free energy calculations for protein-protein complexes under both side-chain and backbone flexibility. Goblin uses a probabilistic graphical model that exploits conditional independencies in the Boltzmann distribution and employs variational inference techniques that approximate the free energy of binding in only a few minutes. We examined the role of conformational entropy on a benchmark set of more than 700 mutants in eight large, well-studied complexes. Our findings suggest that conformational entropy is important in protein-protein interactions—the root mean square error (RMSE) between calculated and experimentally measured ΔΔ Gbinds decreases by 12% when explicit entropic contributions were incorporated. Goblin models all atoms of the protein complex and detects changes to the binding entropy along the interface as well as positions distal to the binding interface. Our results also suggest that a variational approach to entropy calculations may be quantitatively more accurate than the knowledge-based approaches used by the well-known programs Fold-X and Rosetta—Goblin's RMSEs are 10% and 36% lower than these programs, respectively.

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