When a ligand binds to a protein, it is typically not in the lowest-energy conformation for the unbound ligand and there is also a loss of conformational degrees of freedom. The free-energy change for this "conformer focusing" is addressed here formally, and the associated errors with its estimation or neglect are considered in the context of scoring functions for protein-ligand docking and computation of absolute free energies of binding. Specific applications for inhibition of HIV-1 reverse transcriptase are reported. It is concluded that the uncertainties from this source alone are sufficient to preclude the viability of current docking methodology for rank-ordering of diverse compounds in high-throughput virtual screening.