Abstract

Protein binding can induce DNA kinks, which are for example important to enhance the specificity of the interaction and to facilitate the assembly of multi protein complexes. The respective proteins frequently exhibit amino acid sidechains that intercalate between the DNA base steps at the site of the kink. However, on a molecular level there is only little information available about the role of individual sidechains for kink formation. To unravel structural principles of protein-induced DNA kinking we have performed molecular dynamics (MD) simulations of five complexes that varied in their architecture, function, and identity of intercalated residues. Simulations were performed for the DNA complexes of wildtype proteins (Sac7d, Sox-4, CcpA, TFAM, TBP) and for mutants, in which the intercalating residues were individually or combined replaced by alanine. The work revealed that for systems with multiple intercalated residues, not all of them are necessarily required for kink formation. In some complexes (Sox-4, TBP), one of the residues proved to be essential for kink formation, whereas the second residue has only a very small effect on the magnitude of the kink. In other systems (e.g. Sac7d) each of the intercalated residues proved to be individually capable of conferring a strong kink suggesting a partially redundant role of the intercalating residues. Mutation of the key residues responsible for kinking either resulted in stable complexes with reduced kink angles or caused conformational instability as evidenced by a shift of the kink to an adjacent base step. Thus, MD simulations can help to identify the role of individual inserted residues for kinking, which is not readily apparent from an inspection of the static structures. This information might be helpful for understanding protein-DNA interactions in more detail and for designing proteins with altered DNA binding properties in the future.

Highlights

  • The conformational plasticity of DNA is important for essential biological functions like transcription or replication [1, 2]

  • We conducted molecular dynamics (MD) simulations of five complexes that varied in their architecture, function, and identity of intercalated residues

  • Kinked protein-DNA complexes were identified from an analysis of the Nucleic Acid Database (NDB) [31, 32] containing a total of 8617 protein DNA complexes

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Summary

Introduction

The conformational plasticity of DNA is important for essential biological functions like transcription or replication [1, 2]. Deformation of DNA double strands can be facilitated by DNA sequence composition, environmental factors, or by the interaction with proteins [3, 4]. The following introduction will give a brief overview of some global and local types of DNA deformation, which are either observed in free DNA or induced by protein binding. The focus will be on protein-induced DNA kinks, which are the subject of the present study.

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