SAMPL7 Host-Guest Challenge Overview: assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations.
SAMPL7 Host-Guest Challenge Overview: assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations.
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DOI：
10.1007/s10822-020-00363-5
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发表时间：
2021-01
影响因子：
3.5
通讯作者：
Mobley DL
中科院分区：
文献类型：
--
作者：
Amezcua M;El Khoury L;Mobley DL
SAMPL挑战的重点是测试和推动计算方法的进步，以帮助指导药物发现。然而，用于预测结合亲和力的方法的评估通常受到计算挑战的阻碍，例如构象采样、质子化状态不确定性、所选测试集的变化，甚至缺乏高质量的实验数据。因此，SAMPL盲法挑战经常包括关注主客体结合的组分，其消除了这些挑战中的一些，同时仍然关注分子识别。在这里，我们报告了SAMPL 7盲预测挑战的结果，用于主客体亲和力预测。在这项研究中，我们重点关注了三种不同的主宾类别--一种熟悉的深腔洞穴系列，已在之前的几次挑战中出现过（我们研究了一系列客体与两个主体的结合），一系列新的环糊精衍生物，其在边缘周围单官能化以添加氨基酸样功能（其中我们检查两个客体与一系列主体的结合），以及一系列客体与新的无环TrimerTrip主体的结合，该主体与先前的葫芦脲主体相关。许多预测使用了基于分子模拟的方法，总体成功率参差不齐，尽管有几种方法脱颖而出。在SAMPL 6中，我们发现，一个策略，实现合理的准确性，在这里是根据以前的数据，主机类别已经研究过的结合预测进行经验修正，虽然这可能是有限的价值时，新的系统。此外，我们发现，炼金术自由能方法使用AMOEBA极化力场有相当大的成功，他们参与的两个主机类别。还发现新的TrimerTrip系统引入了一些采样问题，因为多种构象可能与结合和相互转化仅缓慢相关。总的来说，这项挑战的结果初步表明，可能需要进一步研究这些挑战的极化力场。
The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories – a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that alchemical free energy methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.
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