McClendon Christopher L, Hua Lan, Barreiro Abriela, Jacobson Matthew P
Graduate Group in Biophysics, University of California San Francisco.
J Chem Theory Comput. 2012 Jul 12;8(6):2115-2126. doi: 10.1021/ct300008d. Epub 2012 Apr 13.
We present a thermodynamical approach to identify changes in macromolecular structure and dynamics in response to perturbations such as mutations or ligand binding, using an expansion of the Kullback-Leibler Divergence that connects local population shifts in torsion angles to changes in the free energy landscape of the protein. While the Kullback-Leibler Divergence is a known formula from information theory, the novelty and power of our implementation lies in its formal developments, connection to thermodynamics, statistical filtering, ease of visualization of results, and extendability by adding higher-order terms. We present a formal derivation of the Kullback-Leibler Divergence expansion and then apply our method at a first-order approximation to molecular dynamics simulations of four protein systems where ligand binding or pH titration is known to cause an effect at a distant site. Our results qualitatively agree with experimental measurements of local changes in structure or dynamics, such as NMR chemical shift perturbations and hydrogen-deuterium exchange mass spectrometry. The approach produces easy-to-analyze results with low background, and as such has the potential to become a routine analysis when molecular dynamics simulations in two or more conditions are available. Our method is implemented in the MutInf code package and is available on the SimTK website at https://simtk.org/home/mutinf.
我们提出了一种热力学方法，用于识别大分子结构和动力学响应诸如突变或配体结合等扰动时的变化，该方法使用Kullback-Leibler散度的展开式，将扭转角的局部种群转移与蛋白质自由能景观的变化联系起来。虽然Kullback-Leibler散度是信息论中的一个已知公式，但我们实现方法的新颖性和强大之处在于其形式发展、与热力学的联系、统计滤波、结果可视化的便利性以及通过添加高阶项的可扩展性。我们给出了Kullback-Leibler散度展开式的形式推导，然后将我们的方法以一阶近似应用于四个蛋白质系统的分子动力学模拟，已知在这些系统中配体结合或pH滴定会在远处位点产生影响。我们的结果在定性上与结构或动力学局部变化的实验测量结果一致，例如核磁共振化学位移扰动和氢-氘交换质谱。该方法产生背景低且易于分析的结果，因此当有两种或更多条件下的分子动力学模拟时，有可能成为一种常规分析方法。我们的方法在MutInf代码包中实现，可在SimTK网站https://simtk.org/home/mutinf上获取。
