Tertiavy structure analysis of biomolecules based on X-ray and NMR data by multicawowical algorithm

我们一直提倡使用蒙特卡罗模拟退火法和多正则算法来预测蛋白质的三级结构。我们一直在尝试从第一原理出发的预测。然而，本项目的目的是证明这些方法也可以用于X射线和核磁共振实验中的结构精细化。在项目的第一年，我们首先介绍了精确包含溶剂效应的RISM理论和组合的RISM和模拟退火法。对于多正则算法，我们首先介绍了RISM理论和模拟退火法。获得模拟的概率因子是非常重要的。因此，开发一种能够容易地确定权重因子的有效方法是很重要的。我们发明了这样一种基于Tsallis统计力学的方法，并用五肽Met-Enkephalin测试了其有效性。在项目的第二年，我们首先开发了基于Tsallis统计机制的上述新方法的分子动力学版本。这一点很重要，由于X-射线和核磁共振实验中的结构修正通常是基于分子动力学方法，因此我们进一步成功地用多克隆模拟方法预测了核糖核酸酶A的C-肽的三级结构，并通过模拟退火法预测了一个牛胰蛋白酶抑制剂片段的三级结构，发现这些模拟结果与X-射线和核磁共振实验结果吻合较好。

We have been advocating the uses of Monte Carlo simulated annealing and multi-canonical algorithms for the prediction of protein tertiary structures.We have been mainly trying the predictions from the first principles.However, it is the purpose of the present project to show that these methods can also be used for the structural refinement in X-ray and NMR experiments.In the first year of the project, we first introduced the RISM theory for accurate inclusion of solvent effects and combined RISM and simulated annealing method.As for multicanonical algorithms, it is non-trivial to obtain the probability factor for simulations.It is thus important to develop an efficient method that allows an easy determination of the weight factor.We have invented such a method based on Tsallis statistical mechanics and tested the effectiveness with a penta peptide, Met-enkephalin.In the second year of the project, we first developed a molecular dynamics version of the above new method that is based on Tsallis statistical mechanics.This is important, since structural refinements in X-ray and NMR experiments are usually based on molecular dynamics method.We further succeeded in the prediction of the tertiary structures of C-peptide of ribonuclease A by multicanonical simulations.We also predicted the tertiary structures of a bovine pancreatic trypsin inhibitor fragment by simulated annealing.It was found that these simulation results are in good agreement with those of X-ray and NMR experiments.