New class of compounds - variators - are reprogramming substrate specificity of H4K12Ac, H4K16Ac and H4K20Ac epigenetic marks reading bromodomain of BPTF protein

TL;DR

This paper demonstrates the computational design of variators that reprogram the substrate specificity of the BPTF bromodomain to recognize different acetylated histone marks, showcasing a new approach for epigenetic target modulation.

Contribution

It provides a detailed computational method for designing variators that reprogram BPTF bromodomain specificity to acetylated histones, expanding the potential for epigenetic therapy.

Findings

Successful reprogramming of BPTF bromodomain specificity demonstrated

Computational approach effectively predicts variator binding modes

Reproducibility of rational design confirmed

Abstract

Previously reported [http://arxiv.org/abs/1506.06433] reprogramming of substrate specificity of H3K4Me3 epigenetic marks reading PHD domain of BPTF protein illustrates therapeutic potential of a new class of non-inhibitor small organic compounds - variators. Here we address the question about reproducibility of rational design of variators by reprogramming of the second epigenetic marks reading domain of BPTF protein - bromodomain. Bromodomain of BPTF binds to epigenetic marks in form of acetylated lysine of histone H4 (H4K12Ac, H4K16Ac and H4K20Ac), which physicochemical properties and binding mode differs considerably from those of methylated H3K4 marks. Thus, detailed description of computational approach for reprogramming of bromodomain substrate specificity illustrates both general and target specific attributes of computer aided variators design.