Plazinska Anita, Plazinski Wojciech, Jozwiak Krzysztof
Department of Chemistry, Faculty of Pharmacy, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, W. Chodzki Street, 4a, 20-093, Lublin, Poland.
J Comput Chem. 2014 Apr 30;35(11):876-82. doi: 10.1002/jcc.23563. Epub 2014 Feb 24.
The computational approach applicable for the molecular dynamics (MD)-based techniques is proposed to predict the ligand-protein binding affinities dependent on the ligand stereochemistry. All possible stereoconfigurations are expressed in terms of one set of force-field parameters [stereoconfiguration-independent potential (SIP)], which allows for calculating all relative free energies by only single simulation. SIP can be used for studying diverse, stereoconfiguration-dependent phenomena by means of various computational techniques of enhanced sampling. The method has been successfully tested on the β2-adrenergic receptor (β2-AR) binding the four fenoterol stereoisomers by both metadynamics simulations and replica-exchange MD. Both the methods gave very similar results, fully confirming the presence of stereoselective effects in the fenoterol-β2-AR interactions. However, the metadynamics-based approach offered much better efficiency of sampling which allows for significant reduction of the unphysical region in SIP.
提出了适用于基于分子动力学（MD）技术的计算方法，以预测取决于配体立体化学的配体-蛋白质结合亲和力。所有可能的立体构型均用一组力场参数[独立于立体构型的势能（SIP）]表示，这使得仅通过单次模拟就能计算所有相对自由能。SIP可通过各种增强采样的计算技术用于研究各种依赖于立体构型的现象。该方法已通过元动力学模拟和副本交换MD在结合四种非诺特罗立体异构体的β2-肾上腺素能受体（β2-AR）上成功进行了测试。两种方法都给出了非常相似的结果，充分证实了非诺特罗与β2-AR相互作用中立体选择性效应的存在。然而，基于元动力学的方法提供了更高的采样效率，这使得SIP中非物理区域得以显著减少。
