Intercalation free energy

Due to the complexity involved, theoretical studies related to intercalation [8, 9] are not common and have been restricted to a main focus of calculating the intercalation free energy, i.e., the free energy difference between intercalated and free states, using a continuum solvent approach [10,11]. These valuable studies have a number of limitations. They involve a very large cancellation of different contributions to the total free energy. Moreover, the molecular level role of water is missing in continuum solvent-based calculations. Finally, no information is provided about the mechanism of the intercalation. 

Free energies of activation to flow increase as the carbonyl group is moved up the hydrocarbon chain. This may relate to the increased ability for intercalation of the molecules as they sit at the water surface. We saw previously that movement of the carbonyl linkage up the hydrocarbon chain... 

P. Cieplak, S. N. Rao, P. D. J. Grootenhuis, and P. A. Kollman, Free energy calculation on base specificity of drug-DNA interactions Application to daunomycin and acridine intercalation into DNA, Biopol. 29 717 (1990). 

These observations, together with those on supercoiled DNAs relaxed by intercalating dyes and by topoisomerase I, indicate that complete conversion from the prevalent secondary structures in supercoiled DNAs to the normal B-helix must be severely hindered kinetically. It is also clear that the free energies per base pair of the secondary structure states a and b must be nearly identical in order for these states to be interconverted by such a small environmental perturbation. 

Consider a cell with some host as one electrode and Li metal as the other. Denote the chemical potential of Li in the host and in Li metal as p and Po, respectively. If the guest has charge ze in the solution of the cell (z = 1 for Li), one ion is intercalated for every z electrons passed through the external circuit. Since the electrons move through the potential difference E, the work done on the cell per ion intercalated is —zeE. This work must equal the change in free energy of the two electrodes, which is p — po), so... 

The intercalation process has been the subject of extensive thermodynamic studies [3,4], providing free energy, entropy and enthalpy differences between the intercalated and free states of various drug molecules. On the other hand, dynamic studies are far less common. Some different aspects of the intercalating molecules have been studied using ultrafast methods [5]. Kinetic studies of drug intercalation are few in number, and a consensus on the mechanism has not been reached [6,7]. Thus, Chaires et al. [6] have proposed a three step model for daunomycin intercalation from the stopped flow association, while Rizzo et al. [7] have proposed a five step kinetic model. 

As described in more detail within, our actual calculations for the intercalation pathway proceeded in a reverse fashion. We calculated free energy changes as the drug was pulled out from the intercalated state and from a minor groove-bound state. The construction of these states is now discussed. 

Two dimensional (2D) Free Energy Landscape of Daunomycin Intercalation... 

While these free energy calculations do not directly address the intercalation dynamics, we could nonetheless discuss [2] this mechanistic picture in the context of the two most extensive experimental kinetic studies [6,7] for dauno-mycin intercalation (which as noted in the Introduction are not in complete accord with each other). We do not enter into the details of this comparison here, but refer the reader to our original article [2]. Suffice it to say here that reasonable accord with some of the kinetics results of Chaires et al. [6] was obtained, and we assigned the first two steps of the three step mechanism of these authors in terms of the two step mechanism we have described above. 

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