Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
J Comput Chem. 2011 Apr 30;32(6):1135-43. doi: 10.1002/jcc.21695. Epub 2010 Nov 29.
Pre-calculated libraries of molecular fragment configurations have previously been used as a basis for both equilibrium sampling (via library-based Monte Carlo) and for obtaining absolute free energies using a polymer-growth formalism. Here, we combine the two approaches to extend the size of systems for which free energies can be calculated. We study a series of all-atom poly-alanine systems in a simple dielectric solvent and find that precise free energies can be obtained rapidly. For instance, for 12 residues, less than an hour of single-processor time is required. The combined approach is formally equivalent to the annealed importance sampling algorithm; instead of annealing by decreasing temperature, however, interactions among fragments are gradually added as the molecule is grown. We discuss implications for future binding affinity calculations in which a ligand is grown into a binding site.
先前已经使用预先计算的分子片段构象库作为平衡采样（通过基于库的蒙特卡罗方法）和使用聚合物增长形式主义获得绝对自由能的基础。在这里，我们将这两种方法结合起来，以扩展可以计算自由能的系统的大小。我们研究了一系列简单介电溶剂中的全原子聚丙氨酸系统，发现可以快速获得精确的自由能。例如，对于 12 个残基，只需要不到一个小时的单处理器时间。组合方法在形式上等同于退火重要性抽样算法；然而，与通过降低温度进行退火不同，随着分子的生长，逐渐添加片段之间的相互作用。我们讨论了在将配体生长到结合位点的情况下进行未来结合亲和力计算的影响。
