Elucidating Solution Structures of Cyclic Peptides Using Molecular Dynamics Simulations.
Elucidating Solution Structures of Cyclic Peptides Using Molecular Dynamics Simulations.
复制标题
DOI：
10.1021/acs.chemrev.0c01087
复制
发表时间：
2021-02-24
期刊：
影响因子：
62.1
通讯作者：
Lin YS
中科院分区：
文献类型：
--
作者：
Damjanovic J;Miao J;Huang H;Lin YS
蛋白质之间的相互作用对生物过程至关重要，但它们界面的形状和大小使它们很难用小分子靶向。环肽作为蛋白质-蛋白质相互作用调节剂具有很高的亲和力和特异性，可与蛋白质表面结合，具有广阔的应用前景。数十种环肽已经获得了FDA的批准，还有更多的环肽正处于不同开发阶段，如免疫抑制剂、抗生素、抗病毒药物或抗癌药物。然而，到目前为止，大多数环肽药物都是天然产物或其衍生物，从头设计已被证明具有挑战性。一个关键的障碍是结构表征：环肽经常在溶液中采用多种构象，这很难用核磁共振光谱等技术来解决。缺乏溶液结构信息阻碍了对环肽序列-结构-功能关系的深入了解。本文综述了强化采样分子动力学模拟技术在环肽溶液结构研究中的应用和发展。我们描述了能够采样环肽构象空间的新的计算方法，并提供了将多肽的序列和结构与生物活性联系起来的计算研究的例子。我们证明，分子动力学模拟已经从一种解释性技术成长为一种成熟的工具，用于环肽治疗设计的前沿的系统研究。
Protein–protein interactions are vital to biological processes, but the shape and size of their interfaces makes them hard to target using small molecules. Cyclic peptides have shown promise as protein–protein interaction modulators, as they can bind protein surfaces with high affinity and specificity. Dozens of cyclic peptides are already FDA-approved, and many more are in various stages of development as immunosuppressants, antibiotics, antivirals, or anticancer drugs. However, most cyclic peptide drugs so far have been natural products or derivatives thereof, with de novo design having proven challenging. A key obstacle is structural characterization: cyclic peptides frequently adopt multiple conformations in solution, which are difficult to resolve using techniques like NMR spectroscopy. The lack of solution structural information prevents a thorough understanding of cyclic peptides’ sequence–structure–function relationship. Here we review recent development and application of molecular dynamics simulations with enhanced sampling to studying the solution structures of cyclic peptides. We describe novel computational methods capable of sampling cyclic peptides’ conformational space and provide examples of computational studies that relate peptides’ sequence and structure to biological activity. We demonstrate that molecular dynamics simulations have grown from an explanatory technique to a full-fledged tool for systematic studies at the forefront of cyclic peptide therapeutic design.
登录
查看更多内容
影响因子：
15
作者：
Beck, Johannes G.;Chatterjee, Jayanta;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
5.5
作者：
Beauchamp, Kyle A.;Lin, Yu-Shan;Das, Rhiju;Pande, Vijay S.
通讯作者：
Pande, Vijay S.
DOI：
10.1073/pnas.251667098
发表时间：
2002-02-19
影响因子：
11.1
作者：
Bennett, JA;Mesfin, FB;Jacobson, HI
通讯作者：
Jacobson, HI
影响因子：
56.9
作者：
ALBERG, DG;SCHREIBER, SL
通讯作者：
SCHREIBER, SL
DOI：
10.1107/s0108768189010633
发表时间：
1990-04-01
影响因子：
1.9
作者：
BARNES, CL;HOSSAIN, MB;VANDERHELM, D
通讯作者：
VANDERHELM, D