Evaluation of Selected Classical Force Fields for Alchemical Binding Free Energy Calculations of Protein-Carbohydrate Complexes

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• 作者：Sushil K. Mishra ; Gaetano Calabr贸 ; Hannes H. Loeffler ; Julien Michel ; Jaroslav Ko膷a
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2015
• 出版时间：July 14, 2015
• 年：2015
• 卷：11
• 期：7
• 页码：3333-3345
• 全文大小：635K
• ISSN：1549-9626

文摘

Protein鈥揷arbohydrate recognition is crucial in many vital biological processes including host鈥損athogen recognition, cell-signaling, and catalysis. Accordingly, computational prediction of protein鈥揷arbohydrate binding free energies is of enormous interest for drug design. However, the accuracy of current force fields (FFs) for predicting binding free energies of protein鈥揷arbohydrate complexes is not well understood owing to technical challenges such as the highly polar nature of the complexes, anomerization, and conformational flexibility of carbohydrates. The present study evaluated the performance of alchemical predictions of binding free energies with the GAFF1.7/AM1-BCC and GLYCAM06j force fields for modeling protein鈥揷arbohydrate complexes. Mean unsigned errors of 1.1 卤 0.06 (GLYCAM06j) and 2.6 卤 0.08 (GAFF1.7/AM1-BCC) kcal路mol^鈥? are achieved for a large data set of monosaccharide ligands for Ralstonia solanacearum lectin (RSL). The level of accuracy provided by GLYCAM06j is sufficient to discriminate potent, moderate, and weak binders, a goal that has been difficult to achieve through other scoring approaches. Accordingly, the protocols presented here could find useful applications in carbohydrate-based drug and vaccine developments.