The binding of proteins to DNA often depends very strongly on the interaction of just a few amino acids with specific base pairs in the DNA.  Understanding the chemical and physical nature of these interactions will provide important insights for the development of pharmaceuticals that can target specific DNA sequences.  Traditional peptides, however, are unlikely to make effective drugs due to the relatively easy hydrolysis of exposed amide bonds in biological systems.  In this work we present a series of molecular dynamics simulations of peptides and peptidomimetic compounds that demonstrate clear sequence-specific DNA-binding ability.  Our results demonstrate that we can use data on atomic fluctuations, interaction energies, and hydrogen bonding patterns to design novel peptidomimetic compounds that retain sequence-specific DNA-binding ability but take advantage of a backbone that will be more stable in a cellular environment.

In silico design of sequence-specific DNA-binding peptidomimetic compounds

244th National Meeting (2012)

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