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성균관대학교

Proc. Natl. Acad. Sci. USA, Feb 04 2025, 122 (5) | https://doi.org/10.1073/pnas.2411316122 Design of a light and Ca2+ switchable organic–peptide hybrid

Zinah Hilal Khaleel ^{1 2 3 †}, Young Hyun No ^{1 3 †}, Nam Hyeong Kim ^{1 3 4 †}, Do Hyun Bae ^{2 5}, Yibing Wu ⁴, Suhyeon Kim ^{1 3}, Hojae Choi ^{1 3}, Da Eun Lee ⁶, Se Yun Jeong ⁶, Yoon-Joo Ko ⁷, Seong-Gi Kim ^{2 5}, Minah Suh^{2 5 8}, Jin-Chul Kim ⁹ ^{10 *}, William F DeGrado ^{4 *}, Ki Hyun Kim^{6 *}, Yong Ho Kim ^{1 2 3 5 8 11 *}

¹SKKU Advanced Institute of Nanotechnology (SAINT), Sungkyunkwan University, Suwon 16419, Republic of Korea.
²Center for Neuroscience Imaging Research, Institute for Basic Science, Suwon 16419, Republic of Korea.
³Department of Nano Science and Technology, Sungkyunkwan University, Suwon 16419, Republic of Korea.
⁴Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94158.
⁵Department of Biomedical Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
⁶School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
⁷Laboratory of Nuclear Magnetic Resonance, National Center for Inter-University Research Facilities, Seoul National University, Seoul 08826, Republic of Korea.
⁸IMNEWRUN Inc., Suwon 16419, Republic of Korea.
⁹Natural Products Research Center, Korea Institute of Science and Technology, Gangneung 25451, Republic of Korea.
¹⁰Division of Bio-Medical Science & Technology, Korea Institute of Science and Technology School, University of Science and Technology, Seoul 02792, Republic of Korea.
¹¹Department of Nano Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.

^†These authors contributed equally
*Corresponding authors: correspondence to Jin-Chul Kim, William F DeGrado, Ki Hyun Kim or Yong Ho Kim

Abstract

The design of organic-peptide hybrids has the potential to combine our vast knowledge of protein design with small molecule engineering to create hybrid structures with complex functions. Here, we describe the computational design of a photoswitchable Ca²⁺-binding organic-peptide hybrid. The designed molecule, designated Ca²⁺-binding switch (CaBS), combines an EF-hand motif from classical Ca²⁺-binding proteins such as calmodulin with a photoswitchable group that can be reversibly isomerized between a spiropyran (SP) and merocyanine (MC) state in response to different wavelengths of light. The MC/SP group acts both as a photoswitch as well as an optical sensor of Ca²⁺ binding. Photoconversion of the SP to the corresponding MC unmasks an acidic phenol, which CaBS uses as an integral part of both its Ca²⁺-binding site as well as its tertiary and quaternary structure. By design, the SP state of CaBS is monomeric, while the Ca²⁺-bound form of the MC state is an obligate dimer, with two Ca²⁺-binding sites formed at the interface of a domain-swapped dimer. Thus, light and Ca²⁺ were expected to serve as an "AND gate" that powers a change in backbone structure/dynamics, oligomerization state, and fluorescence properties of the designed molecule. CaBS was designed using Rosetta and molecular dynamics simulations, and experimentally characterized by nuclear magnetic resonance, isothermal titration calorimetry, and optical titrations. These data illustrate the potential of combining small molecule engineering with de novo protein design to develop sensors whose conformation, association state, and optical properties respond to multiple environmental cues.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-03)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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