期刊
CHEMICAL SCIENCE
卷 12, 期 17, 页码 6107-6116出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0sc06946a
关键词
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资金
- National Natural Science Foundation of China [U1967217, 11574224]
- China Postdoctoral Science Foundation [2019M652052]
- W. M. Keck Foundation [2019-2022]
- National Independent Innovation Demonstration Zone Shanghai Zhangjiang Major Projects [ZJZX2020014]
A recent study revealed that the extension domain of sAPP can bind to the sushi 1 domain of GABA(B)R1a and modulate its synaptic transmission, providing a structural foundation for future drug design. Molecular dynamics simulations and free energy perturbation calculations identified key residues and mutations affecting the binding between sAPP and sushi 1 domain, potentially leading to enhanced GABA(B)R1a modulation. These findings offer new insights into the interactions and may pave the way for the development of GABA(B)R1a-specific therapeutics.
A recent phenomenal study discovered that the extension domain of secreted amyloid-beta precursor protein (sAPP) can bind to the intrinsically disordered sushi 1 domain of the gamma-aminobutyric acid type B receptor subunit 1a (GABA(B)R1a) and modulate its synaptic transmission. The work provided an important structural foundation for the modulation of GABA(B)R1a; however, the detailed molecular interaction mechanism, crucial for future drug design, remains elusive. Here, we further investigated the dynamical interactions between sAPP peptides and the natively unstructured sushi 1 domain using all-atom molecular dynamics simulations, for both the 17-residue sAPP peptide (APP 17-mer) and its minimally active 9 residue segment (APP 9-mer). We then explored mutations of the APP 9-mer with rigorous free energy perturbation (FEP) calculations. Our in silico mutagenesis studies revealed key residues (D4, W6, and W7) responsible for the binding with the sushi 1 domain. More importantly, one double mutation based on different vertebrate APP sequences from evolution exhibited a stronger binding (Delta Delta G = -1.91 +/- 0.66 kcal mol(-1)), indicating a potentially enhanced GABA(B)R1a modulator. These large-scale simulations may provide new insights into the binding mechanism between sAPP and the sushi 1 domain, which could open new avenues in the development of future GABA(B)R1a-specific therapeutics.
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