Childers Matthew Carter, Towse Clare-Louise, Daggett Valerie
Department of Bioengineering, University of Washington, Seattle, WA, USA.
Protein Eng Des Sel. 2018 Jun 1;31(6):191-204. doi: 10.1093/protein/gzy016.
Computational resources have contributed to the design and engineering of novel proteins by integrating genomic, structural and dynamic aspects of proteins. Non-canonical amino acids, such as d-amino acids, expand the available sequence space for designing and engineering proteins; however, the rotamer libraries for d-amino acids are usually constructed as the mirror images of l-amino acid rotamer libraries, an assumption that has not been tested. To this end, we have performed molecular dynamics (MD) simulations of model host-guest peptide systems containing d-amino acids. Our simulations systematically address the applicability of the mirror image convention as well as the effects of neighboring residue chirality. Rotamer libraries derived from these systems provide realistic rotamer distributions suitable for use in both rational and computational design workflows. Our simulations also address the impact of chirality on the intrinsic conformational preferences of amino acids, providing fundamental insights into the relationship between chirality and biomolecular dynamics. While d-amino acids are rare in naturally occurring proteins, they are used in designed proteins to stabilize a desired conformation, increase bioavailability or confer favorable biochemical and physical attributes. Here, we present d-amino acid rotamer libraries derived from MD simulations of alanine-based host-guest pentapeptides and show how certain residues can deviate from mirror image symmetry. Our simulations directly model d-amino acids as guest residues within the chiral l-Ala and d-Ala pentapeptide series to explicitly incorporate any contributions resulting from the chiralities of neighboring residues.
计算资源通过整合蛋白质的基因组、结构和动力学方面，为新型蛋白质的设计和工程做出了贡献。非标准氨基酸，如d-氨基酸，扩展了用于蛋白质设计和工程的可用序列空间；然而，d-氨基酸的旋转异构体文库通常是作为l-氨基酸旋转异构体文库的镜像构建的，这一假设尚未得到验证。为此，我们对含有d-氨基酸的模型主客体肽系统进行了分子动力学（MD）模拟。我们的模拟系统地探讨了镜像惯例的适用性以及相邻残基手性的影响。从这些系统中获得的旋转异构体文库提供了适用于理性和计算设计工作流程的实际旋转异构体分布。我们的模拟还探讨了手性对氨基酸内在构象偏好的影响，为手性与生物分子动力学之间的关系提供了基本见解。虽然d-氨基酸在天然蛋白质中很少见，但它们被用于设计的蛋白质中以稳定所需构象、提高生物利用度或赋予有利的生化和物理特性。在这里，我们展示了从基于丙氨酸的主客体五肽的MD模拟中获得的d-氨基酸旋转异构体文库，并展示了某些残基如何偏离镜像对称。我们的模拟直接将d-氨基酸模拟为手性l-Ala和d-Ala五肽系列中的客体残基，以明确纳入相邻残基手性产生的任何贡献。
