Computationally Assisted Noncanonical Amino Acid Incorporation

Chengzhu Fang; Wenyuan Xu; Chao Liu; Yulin Chen; Shixian Lin; Wenlong Ding

doi:10.1021/acscentsci.4c01544

Computationally Assisted Noncanonical Amino Acid Incorporation

ACS Cent Sci. 2024 Dec 16;11(1):84-90. doi: 10.1021/acscentsci.4c01544. eCollection 2025 Jan 22.

Authors

Chengzhu Fang^{1

2}, Wenyuan Xu^{1

2}, Chao Liu^{1

2}, Yulin Chen^{1

2}, Shixian Lin^{1

2

3

4}, Wenlong Ding^{1

2

5}

Affiliations

¹ The Second Affiliated Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
² Zhejiang Key Laboratory of Molecular Cancer Biology, Center for Life Sciences, Shaoxing Institute, Zhejiang University, Shaoxing 321000, China.
³ Department of Medical Oncology, State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou 310058, China.
⁵ Center for Oncology Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China.

Abstract

Genetic encoding of noncanonical amino acids (ncAAs) with desired functionalities is an invaluable tool for the study of biological processes and the development of therapeutic drugs. However, existing ncAA incorporation strategies are rather time-consuming and have relatively low success rates. Here, we develop a virtual ncAA screener based on the analysis and modeling of the chemical properties of all reported ncAA substrates to virtually determine the recognition potential of candidate ncAAs. Using this virtual screener, we designed and incorporated several novel Lys and Phe derivatives into proteins for various downstream applications. Among them, the genetic encoding of an electron-rich Phe analog, 3-dimethylamino-phenylalanine, was successfully applied to enhance the cation-π interaction between histone methylation and its reader proteins. Thus, our virtual screener provides a fast and powerful strategy to efficiently incorporate ncAAs with diverse functionalities.