All-atom molecular dynamics comparison of disease-associated zinc fingers

Abstract

An important regulatory domain of NF-B Essential Modulator (NEMO) is a ubiquitin-binding zinc finger, with a tetrahedral CYS3HIS1 zinc-coordinating binding site. Two variations of NEMO’s zinc finger are implicated in various disease states including ectodermal dysplasia and adult-onset glaucoma. To discern structural and dynamical differences between these disease states, we present results of 48-s of molecular dynamics simulations for three zinc finger systems each in two states, with and without zinc-bound and correspondingly appropriate cysteine thiol/thiolate configurations. The wild-type protein, often studied for its role in cancer, maintains the most rigid and conformationally stable zinc-bound configuration compared with the diseased counterparts. The glaucoma-related protein has persistent loss of secondary structure except within the dominant conformation. Conformational overlap between wild-type and glaucoma isoforms indicate a competitive binding mechanism may be substantial in the malfunctioning configuration, while the alpha-helical disruption of the ectodermal dysplasia suggests a loss of binding selectivity is responsible for aberrant function.

Keywords:

• zinc fingers
• molecular dynamics
• NEMO
• dysplasia
• glaucoma

Notes

No potential conflict of interest was reported by the authors.

The supplementary material for this paper is available online at https://doi.10.1080/07391102.2017.1363662.

Additional information

Funding

This work was partially supported by National Institutes of Health [grant number R01CA129373] to FRS. The authors wish to acknowledge the support of the Wake Forest Baptist Comprehensive Cancer Center Crystallography & Computational Biosciences Shared Resource, supported by the National Cancer Institutes Cancer Center Support [grant award number P30CA012197]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. RCG acknowledges SCB training National Institute of General Medical Sciences [grant number T32GM095440] for partially supporting this research. FRS also acknowledges a Reynolds Research leave from Wake Forest University. Some computations were performed on the Wake Forest University DEAC Cluster, a centrally managed resource with support provided in part by the University.