Mercadante Davide, Milles Sigrid, Fuertes Gustavo, Svergun Dmitri I, Lemke Edward A, Gräter Frauke
†HITS-Heidelberg Institut for Theoretical Studies, Schloß-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.
‡IWR-Interdisciplinary Center for Scientific Computing, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany.
J Phys Chem B. 2015 Jun 25;119(25):7975-84. doi: 10.1021/acs.jpcb.5b03440. Epub 2015 Jun 15.
Understanding the function of intrinsically disordered proteins is intimately related to our capacity to correctly sample their conformational dynamics. So far, a gap between experimentally and computationally derived ensembles exists, as simulations show overcompacted conformers. Increasing evidence suggests that the solvent plays a crucial role in shaping the ensembles of intrinsically disordered proteins and has led to several attempts to modify water parameters and thereby favor protein-water over protein-protein interactions. This study tackles the problem from a different perspective, which is the use of the Kirkwood-Buff theory of solutions to reproduce the correct conformational ensemble of intrinsically disordered proteins (IDPs). A protein force field recently developed on such a basis was found to be highly effective in reproducing ensembles for a fragment from the FG-rich nucleoporin 153, with dimensions matching experimental values obtained from small-angle X-ray scattering and single molecule FRET experiments. Kirkwood-Buff theory presents a complementary and fundamentally different approach to the recently developed four-site TIP4P-D water model, both of which can rescue the overcollapse observed in IDPs with canonical protein force fields. As such, our study provides a new route for tackling the deficiencies of current protein force fields in describing protein solvation.
理解内在无序蛋白质的功能与我们正确采样其构象动力学的能力密切相关。到目前为止，实验得出的和计算得出的系综之间存在差距，因为模拟显示出过度紧凑的构象。越来越多的证据表明，溶剂在塑造内在无序蛋白质的系综中起着关键作用，并引发了几次修改水参数的尝试，从而使蛋白质 - 水相互作用优于蛋白质 - 蛋白质相互作用。本研究从不同的角度解决这个问题，即使用柯克伍德 - 布夫溶液理论来重现内在无序蛋白质（IDP）的正确构象系综。最近基于此发展的一种蛋白质力场被发现对于从富含FG的核孔蛋白153的一个片段重现系综非常有效，其尺寸与从小角X射线散射和单分子荧光共振能量转移实验获得的实验值相匹配。柯克伍德 - 布夫理论提出了一种与最近开发的四点TIP4P - D水模型互补且根本不同的方法，这两种方法都可以挽救在使用标准蛋白质力场的IDP中观察到的过度塌陷。因此，我们的研究为解决当前蛋白质力场在描述蛋白质溶剂化方面的不足提供了一条新途径。
