Absolute Free Energy of Binding and Entropy of the FKBP12-FK506 Complex: Effects of the Force Field

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• 作者：Ignacio J. General ; Hagai Meirovitch
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：October 8, 2013
• 年：2013
• 卷：9
• 期：10
• 页码：4609-4619
• 全文大小：369K
• 年卷期：v.9,no.10(October 8, 2013)
• ISSN：1549-9626

文摘

The hypothetical scanning molecular dynamics (HSMD) method combined with thermodynamic integration (HSMD-TI) has been extended recently for calculating 螖A⁰鈥攖he absolute free energy of binding of a ligand to a protein. With HSMD-TI, 螖A⁰ is obtained in a new way as a sum of several components, among them is 螖S_ligand鈥攖he change in the conformational entropy as the ligand is transferred from the bulk solvent to the active site鈥攖his entropy is obtained by a specific reconstruction procedure. This unique aspect of HSMD (which is useful in rational drug design) is in particular important for treating large ligands, where 螖S_ligand might be significant. Technically, one should verify that the results for 螖S_ligand converge鈥攁 property that might become more difficult for large ligands; therefore, studying ligands of increasing size would define the range of applicability of HSMD-TI for binding. In this paper, we check the performance of HSMD-TI by applying it to the relatively large ligand FK506 (126 atoms) complexed with the protein FKBP12, where 螖A⁰ = 鈭?2.8 kcal/mol is known experimentally as well as the crystal structure of the complex. This structure was initially equilibrated by carrying out a 100 ns molecular dynamics trajectory, where the system is modeled by the AMBER force field, TIP3P water, and Particle Mesh Ewald. HSMD-TI calculations were carried out in three conformational regions defined by the intervals [0.2,2], [2,5], and [5,100] ns along the trajectory, where local equilibration of the total energy has been observed; we obtained 螖A⁰ = 鈭?3.6 卤 1.1, 鈭?6.6 卤 1.4, and 鈭?6.7 卤 1.4 kcal/mol, respectively indicating the following: (1) The second and third regions belong to the same conformational subspace of the complex, which is different from the [0.2,2] ns subspace. (2) The unsatisfactory result for 螖A⁰ obtained in the well equilibrated (hence theoretically preferred) latter regions reflects the nonperfect modeling used, which however (3) has led to the experimental 螖A⁰ in the [0.2,2] ns region close to the crystal structure. Keeping the complex near its crystal structure has been a successful approach in the literature. To check this avenue further, we applied harmonic restraints on backbone atoms and obtained unsatisfactory results for 螖A⁰, suggesting that implementation of this approach is not straightforward. Converging results for 螖S_ligand were obtained in all regions, where the result 螖S_ligand([0.2,2]) = 7.1 卤 1.2 kcal/mol is less region dependent than 螖A⁰ and is relatively large probably due to the large ligand.