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Transcriptional regulation critically depends on proper interactions between transcription factors (TF) and their cognate DNA binding sites or cis elements. A better understanding and modelling of the TF-DNA interaction is an important area of research. The Positional Weight Matrix (PWM) is the most common model of TF-DNA binding and it presumes that the nucleotide preferences at individual positions within the binding site are independent. However, studies have shown that this independence assumption does not always hold. If the nucleotide preference at one position depends on the nucleotide at another position, a chance mutation at one position should exert selection pressures at the other position. By comparing the patterns of evolutionary conservation at individual positions within cis elements, here we show that positional dependence within binding sites is highly prevalent. We also show that dependent positions are more likely to be functional, as evidenced by a higher information content and higher conservation. We discuss two examples—Elk-1 and SAP-1 where the inferred compensatory mutation is consistent with known TF-DNA crystal structure. [ABSTRACT FROM AUTHOR]