Abstract:
:The prediction of absolute ligand-receptor binding affinities is essential in a wide range of biophysical queries, from the study of protein-protein interactions to structure-based drug design. End-point free energy methods, such as the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) model, have received much attention and widespread application in recent literature. These methods benefit from computational efficiency as only the initial and final states of the system are evaluated, yet there remains a need for strengthening their theoretical foundation. Here a clear connection between statistical thermodynamics and end-point free energy models is presented. The importance of the association free energy, arising from one molecule's loss of translational and rotational freedom from the standard state concentration, is addressed. A novel method for calculating this quantity directly from a molecular dynamics simulation is described. The challenges of accounting for changes in the protein conformation and its fluctuations from separate simulations are discussed. A simple first-order approximation of the configuration integral is presented to lay the groundwork for future efforts. This model has been applied to FKBP12, a small immunophilin that has been widely studied in the drug industry for its potential immunosuppressive and neuroregenerative effects.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Swanson JM,Henchman RH,McCammon JAdoi
10.1016/S0006-3495(04)74084-9subject
Has Abstractpub_date
2004-01-01 00:00:00pages
67-74issue
1 Pt 1eissn
0006-3495issn
1542-0086pii
S0006-3495(04)74084-9journal_volume
86pub_type
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