Multisite λ Dynamics for Protein-DNA Binding Affinity Prediction

Transcription factors (TFs) regulate gene expression by binding to specific DNA sequences, playing a critical role in various cellular processes and diseases. Computational methods, particularly λ Dynamics, offer a promising approach for predicting TF binding affinities. This study evaluates the effectiveness of different λ Dynamics perturbation schemes in determining the binding free energy changes (ΔΔGb) of the WRKY transcription factor upon mutating its W-box binding site (GGTCAA) to a nonspecific sequence (GATAAA). Among the schemes tested, the single λ per base pair protocol demonstrated the fastest convergence and highest precision. Applying this protocol to additional mutations yielded ΔΔGb values that successfully ranked binding affinities, demonstrating a strong potential for high-throughput screening of DNA binding sites.