Estimation of Absolute Protein-DNA Binding Free Energy Using Streamlined Geometric Formalism.

Protein-DNA complexes are involved in vital cellular functions such as gene regulation, replication, transcription, packaging, rearrangement, and damage repair. In this work, we proposed an intricate streamlined geometric formalism for computing the absolute binding free energy, which can be used to obtain chemically accurate in silico estimation of the binding free energy of three protein-DNA complexes. In the formalism, a series of potential of mean force simulations, using the hybrid Gaussian-Accelerated Well-Tempered Metadynamics-Extended Adaptive Biasing Force sampling method (GaWTM-eABF), were performed while harmonically restricting the positional and orientational degrees of freedom involving bound states of the complex, hence attenuating the configuration entropy available to the system and alleviating the sampling limitations. Additionally, analysis of molecular interactions between protein and DNA molecules paints a picture in which hydrogen bonds, electrostatic, van der Waals, π-cation, and hydrophobic interactions were primarily responsible for the association of the protein-DNA complex. Using this formalism, one can obtain the absolute binding free energy for a protein-DNA complex with remarkable accuracy and modest computational cost.