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  • Title: Calculation of configurational entropy with a Boltzmann-quasiharmonic model: the origin of high-affinity protein-ligand binding.
    Author: Harpole KW, Sharp KA.
    Journal: J Phys Chem B; 2011 Aug 04; 115(30):9461-72. PubMed ID: 21678965.
    Abstract:
    Accurate assessment of configurational entropy remains a large challenge in biology. While many methods exist to calculate configurational entropy, there is a balance between accuracy and computational demands. Here we calculate ligand and protein conformational entropies using the Boltzmann-quasiharmonic (BQH) method, which treats the first-order entropy term by the Boltzmann expression for entropy while determining correlations using the quasiharmonic model. This method is tested by comparison with the exact Clausius expression for entropy on a range of test molecules ranging from small ligands to a protein. Using the BQH method, we then analyze the rotational and translational (R/T) entropy change upon ligand binding for five protein complexes to explore the origins of extremely tight affinity. The results suggest that in these systems such affinity is achieved by a combination of simultaneously maintaining good protein-ligand contacts while allowing significant residual R/T motion of the ligand through suitable protein motions.
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