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C5' omitted DNA enhances bendability and protein binding.
1Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India; Supercomputing Facility for Bioinformatics & Computational Biology, Hauz Khas, New Delhi, 110016, India.
Biochemical and Biophysical Research Communications
|May 17, 2019
Summary
Modified DNA structures, C(-) and C(+) nucleic acids, were created to study protein-DNA binding. The highly bendable C(-) DNA showed significantly enhanced protein binding, suggesting therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Protein-DNA interactions are fundamental to cellular function.
- The role of DNA dynamic bendability in these interactions is not fully understood.
- Understanding DNA bendability can offer insights into modulating protein-DNA binding specificity and strength.
Purpose of the Study:
- To investigate the impact of DNA structural modifications on DNA bendability.
- To determine how altered DNA bendability affects protein-DNA binding affinity.
- To explore the therapeutic potential of modified DNA structures with enhanced binding properties.
Main Methods:
- Synthesis of modified nucleic acids (C(-) and C(+)) with altered carbon structures.
- Molecular dynamics (MD) simulations (500 ns) to analyze DNA structural stability and dynamics.
- Energetic calculations and MM-PBSA/GBSA methods to quantify protein-DNA binding affinities.
- DelPhi calculations to assess electrostatic interactions in protein-DNA complexes.
Main Results:
- C(+) nucleic acid maintained a stable B-DNA duplex structure.
- C(-) nucleic acid exhibited significant structural bending.
- Protein binding affinity for C(-) nucleic acid was substantially higher (∼-18 kcal/mol) compared to control (∼-14 kcal/mol) and C(+) nucleic acid.
- Enhanced electrostatic interactions due to exposed bases in C(-) DNA contributed to increased binding.
Conclusions:
- DNA bendability can be modulated through structural modifications, significantly impacting protein binding affinity.
- The C(-) nucleic acid demonstrates a promising model for enhanced protein recognition and binding.
- Modified oligonucleotides show potential for therapeutic applications due to improved protein binding and nuclease resistance.