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Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases

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Abstract

In this work, selectivity mechanism of APP-IP inhibitor (β-amyloid precursor protein-derived inhibitory peptide) over matrix metalloproteinases (MMPs including MMP-2, MMP-7, MMP-9 and MMP-14) was investigated by molecular modeling methods. Among MMPs, MMP-2 is the most favorable one for APP-IP interacting based on our calculations. The predicted binding affinities can give a good explanation of the activity difference of inhibitor APP-IP. In Comparison with MMP-2/APP-IP complex, the side chain of Tyr214MMP-7 makes the binding pocket so shallow that the whole side chain of Tyr3APP-IP can not be fully embraced, thus unfavorable for the N-terminal of APP-IP binding to MMP-7. The poor selectivity of APP-IP toward MMP-9 is mainly related with the decrease of interaction between the APP-IP C-terminal and MMP-9 due to the bulky side chains of Pro193 and Gln199, which is in agreement with experiment. The mutations at residues P193A and Q199G of MMP-9 alternate the binding pattern of the C-terminal of APP-IP by forming two new hydrogen bonds and hydrophobic interactions with MMP-9. The mutants favor the binding affinity of MMP-9 largely. For MMP-14/APP-IP, the large steric effect of Phe204MMP-14 and the weak contributions of the polar residues Asn231MMP-14 and Thr190MMP-14 could explain why MMP-14 is non-selective for APP-IP interacting. Here, the molecular modeling methods were successfully employed to explore the selective inhibitor of MMPs, and our work gives valuable information for future rational design of selective peptide inhibitors toward individual MMP.

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Acknowledgments

We gratefully acknowledge the National Natural Science Foundation of China (No. 21173264) and the Foundation of Knowledge Innovative Engineering of Chinese Academy of Sciences (No. ZNWH-2011-011) for supporting this work.

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Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing, 100049, People’s Republic of China

    Lingling Geng, Jian Gao, Wei Cui, Mingjuan Ji & Bozhen Chen

  2. School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, People’s Republic of China

    Yancheng Tang

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  1. Lingling Geng
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  2. Jian Gao
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  4. Yancheng Tang
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Correspondence to Mingjuan Ji or Bozhen Chen.

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Geng, L., Gao, J., Cui, W. et al. Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases. J Comput Aided Mol Des 26, 1327–1342 (2012). https://doi.org/10.1007/s10822-012-9617-3

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