Hritz Jozef, Oostenbrink Chris
Leiden Amsterdam Center for Drug Research, Division of Molecular Toxicology, VU University Amsterdam, The Netherlands.
J Phys Chem B. 2009 Sep 24;113(38):12711-20. doi: 10.1021/jp902968m.
Compounds with high intramolecular energy barriers represent challenging targets for free energy calculations because of the difficulty to obtain sufficient conformational sampling. Existing approaches are therefore computationally very demanding, thus preventing practical applications for such compounds. We present an enhanced sampling-one step perturbation method (ES-OS) to tackle this problem in a highly efficient way. A single molecular dynamics simulation of a judiciously chosen reference state (using two sets of soft-core interactions) is sufficient to determine conformational distributions of chemically similar compounds and the free energy differences between them. The ES-OS method is applied to a set of five biologically relevant 8-substituted GTP analogs having high energy barriers between the anti and the syn conformations of the base with respect to the ribose part. The reliability of ES-OS is verified by comparing the results to Hamiltonian replica exchange simulations of GTP and 8-Br-GTP and the experimentally determined 3J(C4,H1') coupling constant for GMP in water. Additional simulations in vacuum and octanol allow us to calculate differences in the solvation free energies and in lipophilicities (log P). Free energy contributions from individual conformational regions are also calculated, and their relationship with the overall free energy is derived leading to a set of multiconformational free energy formulas. These relationships are of general applicability and can be used in free energy calculations for a more diverse set of compounds.
由于难以获得足够的构象采样，具有高分子内能量屏障的化合物是自由能计算的挑战性目标。因此，现有方法在计算上要求很高，从而阻碍了此类化合物的实际应用。我们提出了一种增强采样一步扰动方法（ES-OS），以高效地解决这个问题。对精心选择的参考态进行单次分子动力学模拟（使用两组软核相互作用）就足以确定化学相似化合物的构象分布及其之间的自由能差异。ES-OS方法应用于一组五个与生物学相关的8-取代GTP类似物，这些类似物在碱基相对于核糖部分的反式和顺式构象之间具有高能量屏障。通过将结果与GTP和8-Br-GTP的哈密顿量副本交换模拟以及水中GMP的实验测定的3J(C4,H1')耦合常数进行比较，验证了ES-OS的可靠性。在真空和辛醇中的额外模拟使我们能够计算溶剂化自由能和亲脂性（log P）的差异。还计算了各个构象区域的自由能贡献，并推导了它们与总自由能的关系，从而得到一组多构象自由能公式。这些关系具有普遍适用性，可用于更多种类化合物的自由能计算。
