A strategy for proline and glycine mutations to proteins with alchemical free energy calculations.
A strategy for proline and glycine mutations to proteins with alchemical free energy calculations.
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DOI：
10.1002/jcc.26525
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发表时间：
2021-06-05
影响因子：
3
通讯作者：
Brooks CL 3rd
中科院分区：
文献类型：
--
作者：
Hayes RL;Brooks CL 3rd
蛋白质突变的热力学后果的计算在蛋白质生物物理学和设计中具有很大的前景。炼金术的自由能方法可以得到改进的突变自由能的估计，并已被广泛用于计算的相对和绝对结合自由能的小分子设计问题。原则上，炼金术方法可以通过适当的炼金术途径解决任何氨基酸突变，但确定产生脯氨酸和甘氨酸突变的这种途径的策略是一个持续的挑战。目前大多数策略仅干扰侧链原子，而脯氨酸和甘氨酸突变也改变骨架参数和骨架环拓扑结构。一些策略还干扰骨架参数并使甘氨酸突变成为可能。这项工作提出了一种策略，使脯氨酸和甘氨酸突变，包括两个关键要素：一个双骨干与约束和缩放的键合条款，促进骨干参数的变化，和一个软键的脯氨酸环，使环拓扑结构的变化，脯氨酸突变。这些元素在计算机辅助药物设计中也具有核心跳跃和大环研究的实用性。这种新的策略显示出轻微的改进，一套T4溶菌酶突变缺乏脯氨酸和甘氨酸的替代侧链扰动策略，并产生良好的协议与实验的一套T4溶菌酶脯氨酸和甘氨酸突变以前没有研究。据我们所知，这是第一个报告比较炼金术预测脯氨酸突变与实验。有了这个策略，炼金术现在可以获得氨基酸突变的全部调色板。
Computation of the thermodynamic consequences of protein mutations holds great promise in protein biophysics and design. Alchemical free energy methods can give improved estimates of mutational free energies, and are already widely used in calculations of relative and absolute binding free energies in small molecule design problems. In principle, alchemical methods can address any amino acid mutation with an appropriate alchemical pathway, but identifying a strategy that produces such a path for proline and glycine mutations is an ongoing challenge. Most current strategies perturb only side chain atoms, while proline and glycine mutations also alter the backbone parameters and backbone ring topology. Some strategies also perturb backbone parameters and enable glycine mutations. This work presents a strategy that enables both proline and glycine mutations and comprises two key elements: a dual backbone with restraints and scaling of bonded terms, facilitating backbone parameter changes, and a soft bond in the proline ring, enabling ring topology changes in proline mutations. These elements also have utility for core hopping and macrocycle studies in computer-aided drug design. This new strategy shows slight improvements over an alternative side chain perturbation strategy for a set T4 lysozyme mutations lacking proline and glycine, and yields good agreement with experiment for a set of T4 lysozyme proline and glycine mutations not previously studied. To our knowledge this is the first report comparing alchemical predictions of proline mutations with experiment. With this strategy in hand, alchemical methods now have access to the full palette of amino acid mutations.
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