This ERC project is aimed at providing the most comprehensive and complete chemical understanding of the biomolecular recognition processes in epigenetics, using the rigorous physical-organic chemistry as the main approach. Three lines of research have been explored, focusing on biomolecular recognition of methylated lysines, methylated arginines and unstructured histone tails. We have successfully carried out chemical investigations on the recognition of trimethyllysine by epigenetic proteins, by a unique integration of state-of-the-art experimental and computational approaches. Building on basic work on histone peptides, we have incorporated several trimethyllysine analogues into intact histone proteins, and used such designed histone proteins for construction of the higher order octameric histone assembly. We have also developed novel chemical methods for preparation of histones that possess a large panel of dimethylarginine analogues, and for preparation of well-defined cyclic histones. Novel chemical methods developed in this project will provide an important toolbox for future (bio)molecular studies of histones, chromatin-associated proteins, and other proteins of epigenetic importance, with the unprecedented level of molecular detail. As a response to the Covid-19 pandemic, we have successfully designed and developed potent peptides that bind to the spike protein of SARS-CoV-2, thus providing a basis for future research on anti-Covid-19 therapeutics.