Structural changes conserved across the Flap+ complexes, which are more pronounced for the flaps covering the active site, likely contribute to the thermodynamic compensation. The co-crystal structures of Flap+ protease with four of the inhibitors were determined and compared with complexes of both the wild-type protease and another drug-resistant variant that does not exhibit this energetic compensation. Although entropy-enthalpy compensation has been previously observed for a variety of systems, never have changes of this magnitude been reported. This variant (Flap+) has a combination of flap and active site mutations and exhibits extremely large entropy-enthalpy compensation compared to wild-type protease, 5-15 kcal/mol, while losing only 1-3 kcal/mol in total binding free energy for any of six FDA-approved inhibitors. In the current study, profound changes are observed in the binding thermodynamics of a drug-resistant variant compared to wild-type HIV-1 protease, irrespective of the inhibitor bound. While the total enthalpy and entropy change upon binding determine the affinity, often the thermodynamics are considered in terms of inhibitor properties only.

When reading an incomplete chain that is missing one or more residues from PDB, the Wolfram Language will represent it as a sequence of individual subchains.The development of HIV-1 protease inhibitors has been the historic paradigm of rational structure-based drug design, where structural and thermodynamic analyses have assisted in the discovery of novel inhibitors.

Residue sequences given as a list of stringsĪtomic coordinates, typically given in picometersĪll atoms or groups constituting the molecule, typically given as a list of chemical element abbreviations Rules describing the large-scale structure of a chain Spatial resolution of the model coordinates in picometers Residue sequences given as an array of three-letter abbreviations Index of residue atoms in VertexCoordinates and VertexTypes

Index of additional atoms in VertexCoordinates and VertexTypesĪdditional residue sequences given as an array of three-letter abbreviationsĪ symbolic representation of the molecule model Import uses the 'Graphics3D' element by default for the PDB format.Ītoms that are not constituents of a chain.Export uses the 'Rules' element by default.List of rules for options, properties, and settings List of elements and options available in this fileįull list of rules for each element and option

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