human dna polymerase  ( pol   ) 
 plays an essential 
 protective role against skin cancer caused by cyclobutane thymine  thymine 
 dimers ( ttds ) , a frequent form of dna damage arising from exposure 
 to the sun . 
 this enzyme rescues stalled replication forks at the ttds 
 by inserting bases opposite these dna defects . 
 herein we calculate 
 binding free energies for a free deoxyribose nucleotide triphosphate , 
 datp or dgtp , to pol   complexed with undamaged or damaged 
 dna . 
 the calculations indicate that the binding of datp to the enzyme  dna 
 complex 
 is thermodynamically favored for ttd - containing dna over undamaged 
 dna , most likely because of more extensive hydrogen - bonding interactions 
 between the ttd and the enzyme that hold the ttd more rigidly in place . 
 the calculations also illustrate that datp binding is thermodynamically 
 favored over dgtp binding at both thymine positions of the ttd , most 
 likely due to more persistent and stable hydrogen - bonding interactions 
 between the ttd and datp than between the ttd and dgtp . 
 this free 
 energy difference is slightly greater for binding at the 5 
 thymine position than at the 3 thymine position , presumably 
 because of stabilization arising from the a : t base pair formed at 
 the 3 position of the ttd in the previous step of pol   
 function . 
 all of these trends in binding free energies are consistent 
 with experimental measurements of binding strength , fidelity , processivity , 
 and overall efficiency . 
 the insights gained from this analysis have 
 implications for drug design efforts aimed at modifying the binding 
 properties of this enzyme for improving cancer chemotherapy treatments .