Bicyclo-DNA mimics with enhanced protein binding affinities: insights from molecular dynamics simulations

Abstract

DNA-protein interactions occur at all levels of DNA expression and replication and are crucial determinants for the survival of a cell. Several modified nucleotides have been utilized to manipulate these interactions and have implications in drug discovery. In the present article, we evaluated the binding of bicyclo-nucleotides (generated by forming a methylene bridge between C1’ and C5’ in sugar, leading to a bicyclo system with C2’ axis of symmetry at the nucleotide level) to proteins. We utilized four ssDNA-protein complexes with experimentally known binding free energies and investigated the binding of modified nucleotides to proteins via all-atom explicit solvent molecular dynamics (MD) simulations (200 ns), and compared the binding with control ssDNA-protein systems. The modified ssDNA displayed enhanced binding to proteins as compared to the control ssDNA, as seen by means of MD simulations followed by MM-PBSA calculations. Further, the Delphi-based electrostatic estimation revealed that the high binding of modified ssDNA to protein might be related to the enhanced electrostatic complementarity displayed by the modified ssDNA molecules in all the four systems considered for the study. The improved binding achieved with modified nucleotides can be utilized to design and develop anticancer/antisense molecules capable of targeting proteins or ssRNAs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Nucleotide analogs
• protein-DNA recognition
• molecular dynamics simulations
• binding free energies
• electrostatics

Acknowledgements

The authors are thankful to the Department of Biotechnology, Govt of India, and MEITY & CDAC for their support to the Supercomputing Facility for Bioinformatics and Computational Biology (SCFBIO). The authors thank Ms Swati Sharma for her critical reading of the manuscript.

Disclosure statement

There are no conflicts of interest to declare.