Data from: Effects of forcefield and sampling method in all-atom simulations of inherently disordered proteins: Application to conformational preferences of human amylin

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Although several computational modelling studies have investigated the conformational behaviour of inherently disordered protein (IDP) amylin, discrepancies in identifying its preferred solution conformations still exist between various forcefields and sampling methods used. Human islet amyloid polypeptide has long been a subject of research, both experimentally and theoretically, as the aggregation of this protein is believed to be the lead cause of type-II diabetes. In this work, we present a systematic forcefield assessment using one of the most advanced non-biased sampling techniques, Replica Exchange with Solute Tempering (REST2), by comparing the secondary structure preferences of monomeric amylin in solution. This study also aims to determine the ability of common forcefields to sample a transition of the protein from a helical membrane bound conformation into the disordered solution state of amylin. Our results demonstrated that the CHARMM22* forcefield showed the best ability to sample multiple conformational states inherent for amylin. It is revealed that REST2 yielded results qualitatively consistent with experiments and in quantitative agreement with other sampling methods, however far more computationally efficiently and without any bias. Therefore, combining an unbiased sampling technique such as REST2 with a vigorous forcefield testing could be suggested as an important step in developing an efficient and robust strategy for simulating IDPs.

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尽管已有多项计算建模研究探讨了固有无序蛋白（inherently disordered protein, IDP）胰淀素（amylin）的构象行为，但现有不同分子力场（forcefield）与采样方法在确定其偏好溶液构象方面仍存在分歧。人类胰岛淀粉样多肽长期以来都是实验与理论研究的热点对象，因为该蛋白的聚集被认为是II型糖尿病的主要致病诱因。
本研究采用当前最先进的无偏采样技术之一——溶质温度副本交换（Replica Exchange with Solute Tempering, REST2），通过对比溶液中单体胰淀素的二级结构偏好性，系统评估了多种分子力场的表现。本研究同时旨在探究常用分子力场能否准确采样该蛋白从膜结合螺旋构象到胰淀素无序溶液构象的转变过程。
研究结果表明，CHARMM22*力场在采样胰淀素固有的多种构象状态方面表现最优。研究显示，REST2所得结果不仅在定性上与实验数据相符，且与其他采样方法的定量结果一致，同时计算效率显著更高且无任何偏倚。因此，将REST2这类无偏采样技术与严谨的分子力场测试相结合，可被视为开发高效且稳健的固有无序蛋白模拟策略的重要环节。