Atomistic modeling of protein–DNA interaction specificity: progress and applications

An accurate, predictive understanding of protein–DNA binding specificity is crucial for the successful design and engineering of novel protein–DNA binding complexes. In this review, we summarize recent studies that use atomistic representations of interfaces to predict protein–DNA binding specificity computationally. Although methods with limited structural flexibility have proven successful at recapitulating consensus binding sequences from wild-type complex structures, conformational flexibility is likely important for design and template-based modeling, where non-native conformations need to be sampled and accurately scored. A successful application of such computational modeling techniques in the construction of the TAL–DNA complex structure is discussed. With continued improvements in energy functions, solvation models, and conformational sampling, we are optimistic that reliable and large-scale protein–DNA binding prediction and engineering is a goal within reach.

► We review structure-based approaches for protein–DNA binding specificity prediction.
► Interface flexibility is necessary for accurate template-based predictions.
► Assessments on native complexes are likely biased toward conservative approaches.
► Applications to structure determination and protein design are discussed.