Special considerations regarding ligands binding to HIV-1 protease

Special Considerations Regarding Ligands Binding to HIV-1 Protease 

The continued derivation now shifts to the more specific problem of a ligand binding to wild type HIV-1 protease and its mutants. In this case P will be now be called and P will be called P,, y, where WT and MU stand for wild type and mutant protease respectively. HIV-1 protease is composed of two noncovalently associated structurally identical monomers, the active site contains two conserved catalytic aspartic acid residues, one from each monomer. Furthermore, the active site is C2 symmetric. Any active site mutation will result in structural effects in two different locations, one on each monomer, therefore, mutation does not break the C2 symmetry. As a result of these considerations, we can assume that the symmetry numbers for P,. and P are the same. This will also hold for LP, and LP. The ratio of symmetry numbers will then be equal to unity and the natural logarithm then zeros out the first term of equation (15). 

Approximation 2 Assume that the volume differences are so small that the PV work done on or by the system due changes in volume upon binding can be neglected. This approximation will be very good because most mutations of HIV-1 protease involve a single residue change on each monomer. Hence P, and P ,jj are nearly identical and we can ignore the pressure volume term of equation (15). 

E can be calculated using standard molecular mechanics potentials [30] and is 

and A(U), is the van der Waals surface area of the residue i side chain in isolation, i.e., the residue alone with the rest of the protein removed. The parameter a. is taken from the entropy scale of Pickett and Sternberg [27]. It is an estimate of the side-chain folding entropy of residue i or the entropic burden incurred when residue i is taken from an exposed state at the surface of the protein and buried within the protein. Pickett and Sternberg [27] estimated the a. values for all 20 amino acids by analyzing the torsional preferences of surface exposed side-chains relative to buried side chains. This analysis was performed over a set of 50 non-homologous protein crystal structures which included HIV-1 protease. 

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