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Experimental melting transitions of several natural DNAs of known nucleotide sequences have recently been obtained. The differential melting curves of these DNAs-phi X174 DNA, fd DNA and SV40 DNA-all show distinctive sets of peaks or fine structure. Theoretical melting curves calculated from the sequences and a few a priori parameters have not accurately predicted the experimental transitions. Although calculated fine structure resembled experimental curves in some cases, the characteristic features of a DNA's differential melting curve could not generally be produced. Azbel and Gabbarro-Arpa et al. have recently obtained good agreement between calculated and experimental curves using a different theoretical approach-only ground-state configurations of DNA were considered for temperatures inside the transition region. Their results suggest that the basic model of DNA melting, common to all theoretical approaches, is accurate. We have used here an exact theoretical approach to calculated melting curves of four DNA restriction fragments of 95-301 base pairs containing the lactose promoter region (Fig. 1). Theoretical curves agree very well with the experimental transitions published by Hardies et al. and obtained in this laboratory.