Comparison of the ligand binding site of C1 domains: a molecular dynamics simulation study of the C1 domain–phorbol 13-acetate–membrane system

Abstract

C1 domains are lipid-binding structural units of about 50 residues. Typical C1 domains associate with the plasma membrane and bind to diacylglycerol/phorbol ester during the activation of the proteins containing these domains. Although the overall structure of the C1 domains are similar, there are differences in their primary sequence and in the orientation of the ligand/lipid binding residues. To gain structural insights into the ligand/lipid binding, we performed molecular docking of phorbol 13-acetate into the C1 domain and 1.0 μs molecular dynamics simulation on the C1 domain–ligand–lipid ternary system for PKCθ C1A, PKCδ C1B, PKCβII C1B, PKCθ C1B, Munc13-1 C1, and βII-Chimaerin C1. We divided these C1 domains into three types based on the orientations of Gln-27 and Trp/Tyr-22. In type 1, Trp/Tyr-22 is outside and Gln-27 is inside the ligand binding pocket. In type 2, both Trp/Tyr-22 and Gln-27 are outside the ligand binding pocket, and in type 3, Trp/Tyr-22 is inside and Gln-27 is outside the pocket. The type 1 C1 domains showed higher ligand binding and higher membrane binding with a shorter distance between the C1 domain and the membrane than the type 2 and type 3. For ligand binding, Pro-11 plays a major role in the type 1 and 2, and Gly-23 in the type 1 and type 3 C1 domains. This study elucidates the role of Gln-27, Trp-22, Pro-11 and Gly-23 in ligand/lipid binding in typical C1 domains and bears significance in developing selective modulators of C1 domain-containing proteins.

Communicated by Ramaswamy H. Sarma

Keywords:

• C1 domain
• molecular docking
• molecular dynamics
• presynaptic
• Munc13-1
• lipid membrane
• phorbol ester
• diacylglycerol

Acknowledgements

MD simulations were performed using the server at the Center for Advanced Computing and Data Systems (CACDS) of the University of Houston.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

JD designed, and YY and KM performed the study. JD, YY and KM wrote the paper.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research has been supported by funding from National Institutes of Health Grants, 1R01AA022414 to J.D.