Zerze Gül H, Zheng Wenwei, Best Robert B, Mittal Jeetain
Department of Chemical and Biomolecular Engineering , Lehigh University , Bethlehem , Pennsylvania 18015 , United States.
College of Integrative Sciences and Arts , Arizona State University , Mesa , Arizona 85212 , United States.
J Phys Chem Lett. 2019 May 2;10(9):2227-2234. doi: 10.1021/acs.jpclett.9b00850. Epub 2019 Apr 22.
Experimental studies on intrinsically disordered and unfolded proteins have shown that in isolation they typically have low populations of secondary structure and exhibit distance scalings suggesting that they are at near-theta-solvent conditions. Until recently, however, all-atom force fields failed to reproduce these fundamental properties of intrinsically disordered proteins (IDPs). Recent improvements by refining against ensemble-averaged experimental observables for polypeptides in aqueous solution have addressed deficiencies including secondary structure bias, global conformational properties, and thermodynamic parameters of biophysical reactions such as folding and collapse. To date, studies utilizing these improved all-atom force fields have mostly been limited to a small set of unfolded or disordered proteins. Here, we present data generated for a diverse library of unfolded or disordered proteins using three progressively improved generations of Amber03 force fields, and we explore how global and local properties are affected by each successive change in the force field. We find that the most recent force field refinements significantly improve the agreement of the global properties such as radii of gyration and end-to-end distances with experimental estimates. However, these global properties are largely independent of the local secondary structure propensity. This result stresses the need to validate force fields with reference to a combination of experimental data providing information about both local and global structure formation.
对内在无序和未折叠蛋白质的实验研究表明，它们在孤立状态下通常具有低比例的二级结构，并呈现出距离标度，这表明它们处于接近θ溶剂的条件。然而，直到最近，全原子力场仍无法再现内在无序蛋白质（IDP）的这些基本特性。最近通过针对水溶液中多肽的系综平均实验观测值进行优化，解决了包括二级结构偏差、全局构象特性以及折叠和塌缩等生物物理反应的热力学参数等不足之处。迄今为止，利用这些改进的全原子力场的研究大多局限于一小部分未折叠或无序的蛋白质。在此，我们展示了使用三代逐步改进的Amber03力场为一个多样化的未折叠或无序蛋白质文库生成的数据，并探讨了力场的每次连续变化如何影响全局和局部特性。我们发现，最近的力场优化显著提高了诸如回转半径和端到端距离等全局特性与实验估计值的一致性。然而，这些全局特性在很大程度上与局部二级结构倾向无关。这一结果强调了需要参考提供有关局部和全局结构形成信息的实验数据组合来验证力场。
