Abstract
Recognition of single-stranded DNA (ssDNA) or single-stranded RNA (ssRNA) is important for many fundamental cellular functions. A variety of single-stranded DNA-binding proteins (ssDBPs) and single-stranded RNA-binding proteins (ssRBPs) have evolved that bind ssDNA and ssRNA, respectively, with varying degree of affinities and specificities to form complexes. Structural studies of these complexes provide key insights into their recognition mechanism. However, computational modeling of the specific recognition process and to predict the structure of the complex is challenging, primarily due to the heterogeneity of their binding energy landscape and the greater flexibility of ssDNA or ssRNA compared with double-stranded nucleic acids. Consequently, considerably fewer computational studies have explored interactions between proteins and single-stranded nucleic acids compared with protein interactions with double-stranded nucleic acids. Here, we report a newly developed energy-based coarse-grained model to predict the structure of ssDNA–ssDBP and ssRNA–ssRBP complexes and to assess their sequence-specific interactions and stabilities. We tuned two factors that can modulate specific recognition: base–aromatic stacking strength and the flexibility of the single-stranded nucleic acid. The model was successfully applied to predict the binding conformations of 12 distinct ssDBP and ssRBP structures with their cognate ssDNA and ssRNA partners having various sequences. Estimated binding energies agreed well with the corresponding experimental binding affinities. Bound conformations from the simulation showed a funnel-shaped binding energy distribution where the native-like conformations corresponded to the energy minima. The various ssDNA–protein and ssRNA–protein complexes differed in the balance of electrostatic and aromatic energies. The lower affinity of the ssRNA–ssRBP complexes compared with the ssDNA–ssDBP complexes stems from lower flexibility of ssRNA compared to ssDNA, which results in higher rate constants for the dissociation of the complex (koff) for complexes involving the former.
Highlights
Interactions between nucleic acids and proteins are essential and central to many biochemical processes
Quantifying bimolecular self-assembly is pivotal to understanding cellular function
Different single-stranded DNA-binding proteins (ssDBPs) and single-stranded RNA-binding proteins (ssRBPs) perform different cellular functions, the actual number of distinct domains found in both cases is limited
Summary
Interactions between nucleic acids and proteins are essential and central to many biochemical processes. Protein–nucleic acid complexes have very diverse structures and the interface may depend on both the shape of the protein and the structure of the nucleic acid. An RNA strand can fold into diverse three-dimensional (3D) structures, including double-stranded A-form helices and higherorder tertiary structures [3] that interact with proteins. Stable complexes between proteins and nucleic acids are essential and their disruption can lead to a range of diseases [4], including several neurodegenerative disorders [5] and cancers [6]. Structures between proteins and single-stranded (ss) DNA and RNA are essential for function, for example, in telomeric overhangs at the end of chromosomes, at double stranded breaks, and at replication forks [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
