Melting of cross-linked DNA IV. Methods for computer modeling of total influence on DNA melting of monofunctional adducts, intrastrand and interstrand cross-links formed by molecules of an autitumor drug.

A theoretical method is developed for calculation of melting curves of cova lent complexes of DNA with antitumor drugs. The method takes into account a ll the types of chemical modifications of the double helix caused by platin um compounds and DNA alkylating agents: 1) monofunctional adducts bound to one nucleotide; 2) intrastrand cross-links which appear due to bidentate bi nding of a drug molecule to two nucleotides that are included into the same DNA strand; 3) interstrand cross-links caused by bidentate binding of a mo lecule to two nucleotides of different strands. The developed calculation m ethod takes into account the following double helix alterations at sites of chemical modifications: 1) a change in stability of chemically modified ba se pairs and neighboring ones, that is caused by all the types of chemical modifications; 2) a change in the energy of boundaries between helical and melted regions at sites of chemical modification (local alteration of the f actor of cooperativity of DNA melting), that is caused by all the types of chemical modifications, too; 3) a change in the loop entropy factor of melt ed regions that include interstrand cross-links; 4) the prohibition of dive rgence of DNA strands in completely melted DNA molecules, which is caused b y interstrand cross-links only. General equations are derived, and three ca lculation methods are proposed to calculate DNA melting curves and the para meters that characterize the helix-coil transition.