An Integrated Framework Advancing Membrane Protein Modeling and Design.
An Integrated Framework Advancing Membrane Protein Modeling and Design.
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DOI：
10.1371/journal.pcbi.1004398
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发表时间：
2015-09
影响因子：
4.3
通讯作者：
Gray JJ
中科院分区：
文献类型：
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作者：
Alford RF;Koehler Leman J;Weitzner BD;Duran AM;Tilley DC;Elazar A;Gray JJ
膜蛋白是人体中的关键功能分子，构成人类基因组中超过30%的开放阅读框。不幸的是，在过表达和重组成膜模拟物中的无数困难严重限制了我们确定其结构的能力。因此，计算工具有助于膜蛋白结构预测，从而增加我们对膜蛋白功能及其在疾病中的作用的理解。在这里，我们描述了一个通用的框架，促进膜蛋白建模和设计，结合膜蛋白建模的科学原理与灵活的软件架构Rosetta 3。这个新的框架，称为RosettaMP，提供了一个通用的膜表示，与评分，构象采样和突变程序，可以很容易地结合起来创建新的协议接口。为了展示该实现的功能，我们开发了四个概念验证应用程序：（1）预测突变后的自由能变化;（2）高分辨率结构细化;（3）蛋白质-蛋白质对接;（4）对称蛋白质复合物的组装，所有这些都在膜环境中进行。初步数据表明，这些算法可以产生有意义的分数和结构。数据还表明，需要改进的采样程序和评分功能。重要的是，这些应用程序共同展示了将RosettaMP的灵活性与Rosetta算法的强大功能相结合以促进膜蛋白建模和设计的潜力。超过30%的人类蛋白质组由嵌入生物膜的蛋白质组成。这些蛋白质在许多过程中至关重要，例如将材料运输进出细胞以及将信号传输到体内的其他细胞。它们与许多疾病有关;事实上，它们是市场上超过50%的药物的目标。由于膜环境使得实验结构确定非常困难，因此需要替代的计算方法。在这里，我们描述了一个新的框架，RosettaMP，膜蛋白结构的计算建模和设计，集成在Rosetta 3软件套件。这个框架包括一套工具，用于表示膜双层，移动蛋白质，改变其序列，并估计自由能。我们展示的工具来预测突变的影响，细化蛋白质结构的原子细节，模拟蛋白质结合，并组装对称复合物，所有在膜双层。总之，这些应用证明了RosettaMP促进膜蛋白结构预测和设计的潜力，使我们能够了解这些蛋白质的功能及其在人类疾病中的作用。
Membrane proteins are critical functional molecules in the human body, constituting more than 30% of open reading frames in the human genome. Unfortunately, a myriad of difficulties in overexpression and reconstitution into membrane mimetics severely limit our ability to determine their structures. Computational tools are therefore instrumental to membrane protein structure prediction, consequently increasing our understanding of membrane protein function and their role in disease. Here, we describe a general framework facilitating membrane protein modeling and design that combines the scientific principles for membrane protein modeling with the flexible software architecture of Rosetta3. This new framework, called RosettaMP, provides a general membrane representation that interfaces with scoring, conformational sampling, and mutation routines that can be easily combined to create new protocols. To demonstrate the capabilities of this implementation, we developed four proof-of-concept applications for (1) prediction of free energy changes upon mutation; (2) high-resolution structural refinement; (3) protein-protein docking; and (4) assembly of symmetric protein complexes, all in the membrane environment. Preliminary data show that these algorithms can produce meaningful scores and structures. The data also suggest needed improvements to both sampling routines and score functions. Importantly, the applications collectively demonstrate the potential of combining the flexible nature of RosettaMP with the power of Rosetta algorithms to facilitate membrane protein modeling and design. Over 30% of the human proteome consists of proteins embedded in biological membranes. These proteins are critical in many processes such as transport of materials in and out of the cell and transmitting signals to other cells in the body. They are implicated in a large number of diseases; in fact, they are targeted by over 50% of pharmaceutical drugs on the market. Since the membrane environment makes experimental structure determination extremely difficult, there is a need for alternative, computational approaches. Here, we describe a new framework, RosettaMP, for computational modeling and design of membrane protein structures, integrated in the Rosetta3 software suite. This framework includes a set of tools for representing the membrane bilayer, moving the protein, altering its sequence, and estimating free energies. We demonstrate tools to predict the effects of mutations, refine atomic details of protein structures, simulate protein binding, and assemble symmetric complexes, all in the membrane bilayer. Taken together, these applications demonstrate the potential of RosettaMP to facilitate membrane protein structure prediction and design, enabling us to understand the function of these proteins and their role in human disease.
影响因子：
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作者：
Dukka BK
通讯作者：
Dukka BK