Pacholczyk Marcin, Kimmel Marek
Silesian University of Technology, Gliwice, Poland.
J Comput Biol. 2011 Jun;18(6):843-50. doi: 10.1089/cmb.2010.0017. Epub 2010 Nov 20.
Analysis of protein/small molecule interactions is crucial in the discovery of new drug candidates and lead structure optimization. Small biomolecules (ligands) are highly flexible and may adopt numerous conformations upon binding to the protein. Using computer simulations instead of sophisticated laboratory procedures may significantly reduce cost of some stages of drug development. Inspired by probabilistic path planning in robotics, stochastic roadmap methodology can be regarded as a very interesting approach to effective sampling of ligand conformational space around a protein molecule. Protein-ligand interactions are divided into two parts: electrostatics, modeled by the Poisson-Boltzmann equation, and van der Waals interactions, represented by the Lennard-Jones potential. The results are promising; it can be shown that locations of binding sites predicted by the simulation are in agreement with those revealed by experimental x-ray crystallography of protein-ligand complexes. We wanted to extend our knowledge beyond the current molecular modeling tools to arrive at a better understanding of the ligand-binding process. To this end, we investigated a two-level model of protein-ligand interaction and sampling of ligand conformational space covering the entire surface of protein target.
蛋白质/小分子相互作用的分析对于发现新的候选药物和先导结构优化至关重要。小生物分子（配体）具有高度的灵活性，在与蛋白质结合时可能会采取多种构象。使用计算机模拟而非复杂的实验室程序可以显著降低药物开发某些阶段的成本。受机器人技术中概率路径规划的启发，随机路图方法可被视为一种非常有趣的方法，用于对蛋白质分子周围配体构象空间进行有效采样。蛋白质-配体相互作用分为两部分：由泊松-玻尔兹曼方程建模的静电作用，以及由 Lennard-Jones 势表示的范德华相互作用。结果很有前景；可以证明，模拟预测的结合位点位置与蛋白质-配体复合物的实验 X 射线晶体学揭示的位置一致。我们希望将知识扩展到当前的分子建模工具之外，以便更好地理解配体结合过程。为此，我们研究了蛋白质-配体相互作用的两级模型以及覆盖蛋白质靶标整个表面的配体构象空间采样。
