Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials
Absolute binding free energy calculations using molecular dynamics simulations with restraining potentials
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DOI：
10.1529/biophysj.106.084301
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发表时间：
2006-10-01
影响因子：
3.4
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Wang, Jiyao;Deng, Yuqing;Roux, Benoit
利用自由能摄动分子动力学（FEP/MD）模拟计算了8种fk506相关配体与FKBP12的绝对（标准）结合自由能。为了提高精度和增强计算的收敛性，实现了许多特征。首先，将绝对结合自由能分解为连续的步骤，在此过程中，配体与周围的相互作用以及抑制配体的平移、取向和构象的各种偏置势被“打开”和“关闭”。其次，配体构象的采样是通过一个基于相对于束缚态构象的均方根偏差的约束势来实现的。所有约束势的作用都是严格无偏的，并明确表明最终结果不受所有人为约束的影响。第三，利用Weeks-Chandler-Andersen分离计算配体与其周围（蛋白质和溶剂）的Lennard-Jones相互作用产生的排斥力和色散自由能贡献。这种分离也提高了fep /MD计算的收敛性。第四，为了降低计算成本，采用广义溶剂边界势（GSBP）方法，只显式地模拟结合位点附近的少量原子，而隐式地考虑其余原子的影响。使用GSBP，模拟的FKBP12/配体系统的尺寸显着减小，从类似的25,000减小到2500。计算效率高，统计误差小（近似于1 kcal/mol）。计算得到的束缚自由能与现有的实验数据和以前的计算结果基本一致（在2千卡/摩尔范围内）。目前的结果表明，基于FEP/MD模拟的简化GSBP原子模型具有构象、平动和取向抑制势，计算成本低且准确。
The absolute (standard) binding free energy of eight FK506-related ligands to FKBP12 is calculated using free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent. A number of features are implemented to improve the accuracy and enhance the convergence of the calculations. First, the absolute binding free energy is decomposed into sequential steps during which the ligand-surrounding interactions as well as various biasing potentials restraining the translation, orientation, and conformation of the ligand are turned "on'' and "off.'' Second, sampling of the ligand conformation is enforced by a restraining potential based on the root mean-square deviation relative to the bound state conformation. The effect of all the restraining potentials is rigorously unbiased, and it is shown explicitly that the final results are independent of all artificial restraints. Third, the repulsive and dispersive free energy contribution arising from the Lennard-Jones interactions of the ligand with its surrounding (protein and solvent) is calculated using the Weeks-Chandler-Andersen separation. This separation also improves convergence of theFEP/MD calculations. Fourth, to decrease the computational cost, only a small number of atoms in the vicinity of the binding site are simulated explicitly, while all the influence of the remaining atoms is incorporated implicitly using the generalized solvent boundary potential (GSBP) method. With GSBP, the size of the simulated FKBP12/ligand systems is significantly reduced, from similar to 25,000 to 2500. The computations are very efficient and the statistical error is small (similar to 1 kcal/mol). The calculated binding free energies are generally in good agreement with available experimental data and previous calculations (within similar to 2 kcal/mol). The present results indicate that a strategy based on FEP/MD simulations of a reduced GSBP atomic model sampled with conformational, translational, and orientational restraining potentials can be computationally inexpensive and accurate.