Multisite λ-Dynamics for Protein–DNA Binding Affinity Prediction
Transcription factors (TFs) regulate gene expression by binding to specific DNA sequences, playing critical roles in cellular processes and disease pathways. Computational methods, particularly λ-Dynamics, offer a promising approach for predicting TF relative binding affinities. This study evaluates the effectiveness of different λ-Dynamics perturbation schemes in determining binding free energy changes (ΔΔ<i>G</i><sub><i>b</i></sub>) of the WRKY transcription factor upon mutating its W-box binding site (G<u>G</u>T<u>C</u>AA) to a nonspecific sequence (G<u>A</u>T<u>A</u>AA). Among the schemes tested, the single λ per base pair protocol demonstrated the fastest convergence and highest precision. Extending this protocol to additional mutants (GGTC<u>C</u><u>G</u> and GG<u>A</u>CAA) yielded ΔΔ<i>G</i><sub><i>b</i></sub> values that successfully ranked binding affinities, showcasing its strong potential for high-throughput screening of DNA binding sites.
Authors
- Jin Yu (ORCID: https://orcid.org/0000-0001-8224-1374)
- Jonah Z. Vilseck (ORCID: https://orcid.org/0000-0001-7076-8996)
- Ryan L. Hayes (ORCID: https://orcid.org/0000-0003-1052-6391)
- Carmen Al Masri (ORCID: https://orcid.org/0009-0005-3985-5051)
Institutions
- University of California, Irvine (US)
- University of California System (US)
- Institut thématique Génétique, génomique et bioinformatique (FR)
- Astronomy and Space (AU)
- University School (US)
- Pharmaceutical Biotechnology (Czechia) (CZ)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Indiana University (US)
Publication Details
- Journal
- Journal of Chemical Theory and Computation
- Published
- 2025-03-24
- DOI
- https://doi.org/10.1021/acs.jctc.4c01408
- Citations
- 2
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Cancer Research Coordinating Committee
- National Institute of General Medical Sciences