THE MOLECULAR ASPECT OF NUCLEIC ACID 

 INTERACTIONS 



Paul 0. P. Ts'o 



Department of Radiological Sciences, The Johns Hopkins University, 

 Baltimore, Maryland 



The underlying philosophy and the strategy 

 of our research is quite different from that 

 presented in this workshop so far. We are 

 interested in solving the problem of biology from 

 the standpoint of chemistry and the approach of 

 chemistry, especially physical chemistry. The 

 experimental system usually consists of simple 

 models. The approach is analytical and quantita- 

 tive. The conclusion is generally unambiguous 

 and mechanistic in nature. This is the power or 

 the characteristic of physical sciences. Our 

 problems are, however, oversimplification and 

 unrealism. The conclusion may not be relevant 

 to the more complex situation in biology in which 

 we are interested. The major challenge to our 

 work, therefore, is the meaningfulness of our re- 

 sults to the central problems of biology. We have 

 to walk on a tight rope. On one hand, the system 

 has to be simple enough to be analyzed quantita- 

 tively from the standpoint of physical sciences. 

 On the other hand, the system has to be compli- 

 cated enough and sophisticated enough to contain 

 the essence of the biological world. I hope to 

 demonstrate to you how we try to meet both de- 

 mands in our research. 



From the standpoint of chemistry, study of 

 the biological system can be viewed as the study 

 of the structures, properties and interactions of 

 biopolymers, with themselves and with small 

 molecules. Of all biopolymers, proteins and 

 nucleic acids appear to be the most important 

 in terms of the specific interactions which lead 

 to information transfer. 



The significance and some of the general 

 principles of the interactions of nucleic acids 

 with one another are well known. These concepts 

 and this knowledge have served as the foundation 

 for the development of molecular genetics. We 

 wish to reexamine quantitatively the basic prin- 



ciples and the nature of the forces which govern 

 the interactions of nucleic acids, and to do so by 

 physical chemical studies. 



The problem is approached at three levels of 

 complexity: (1) interaction in solution between 

 the monomeric units of nucleic acid and their 

 analogs and derivatives; (2) interaction between 

 the monomeric units and the nucleic acid 

 polymer; (3) interaction between nucleic acid 

 polymers. The present review is confined to 

 investigations at the first two levels. 



We concentrate first on interactions of neu- 

 tral compounds and thus avoid complications due 

 to the strong electrostatic interactions of 

 charged molecules. Because both the sugar and 

 the phosphate moieties are common to all 

 nucleotide units, specific interactions of nucleic 

 acids must reside in the purine and pyrimidine 

 bases. Therefore, the experimental approach 

 may quite justifiably be focused on the interaction 

 of uncharged bases and nucleosides and their 

 interaction with nucleic acid polymers. 



The first level of interaction includes the 

 following problems: Does a solution of mono- 

 meric units, such as free nucleosides, interact 

 within itself? To what extent? By what mech- 

 anism? To answer these questions, three types 

 of physical- chemical measurements have been 

 made using, because of solubility problems, 

 pyrimidine nucleosides and purine. 



Vapor pressures of solutions of purine, 

 uridine, cytidine, 5-bromouridine, and 6- 

 methylpurine, from 0.1 molal to approximately 

 0,8 molal have been measured thermoelec- 

 trically (1, 2). Osmotic coefficients, 0, were 

 calculated from the data (Table I). Activity 

 coefficients at 25° were calculated from the 

 osmotic coefficients by the Gibbs-Diihem rela- 

 tionship using a computer which performed a 



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