The Forces Between Protein Molecules in 

 Solution 



John G. Kirkwood 



Yale University, New Haven, Conn. 



UNTIL THERE IS CONVINCING EVIDENCE to the Contrary, it is reasonable 

 to accept the hypothesis that the forces between protein molecules 

 are of the same nature as those acting between simple molecules of 

 low molecular weight. At small intermolecular distances quantum mechanical 

 exchange produces a repulsion which determines the size and shape of the 

 molecules. At larger distances the London dispersion forces act to produce a 

 general van der Waals attraction. Moreover, since proteins are amphoteric 

 polymers of the highly polar amino acids, many of which possess acidic or 

 basic side chains, the molecules undoubtedly possess characteristic distribu- 

 tions of electric charge which give rise to strong electrostatic interactions. 

 Evidence for the dominant role of electrostatic forces is provided by the sensi- 

 tivity of the thermodynamic interaction of protein molecules to ionic strength. 

 The reduction in interaction with increasing ionic strength, frequently ob- 

 served, is produced by the screening action of the statistical space charge of 

 the electrolytic environment. It is easy to demonstrate that such screening 

 could be effective only on that part of the interaction which is electrostatic 

 in origin and not on the high frequency exchange forces and van der Waals 

 forces. 



Although of the same basic origin as those between simple molecules, the 

 forces between protein molecules possess special features arising from their 

 complex sturctural organization. These special features relate to the pattern 

 of arrangement of the structural elements responsible for the specificity of 

 interaction and to the mobility of the charges responsible for electrostatic 

 interaction. The special forces arising from the mobility of the charge distribu- 

 tions have received theoretical treatment by Kirkwood and Shumaker (1952). 

 They will be the principal subject of this discussion. Proteins, considered as 

 ampholites, contain a large number of neutral and negatively charged basic 

 groups, for example, NH2 and COO — , to which protons are bound to a degree 

 determined by the pH. Except in highly acid solutions, the number of basic 

 sites generally exceeds the number of protons bound to the molecule so that 



^ Summary of a lecture presented at the symposium, "Molecular Structure and 

 Biological Specificity" in Washington, D. C, March 1955 and at the symposium on 

 BiocoUoids in Gatlinburg, Tennessee in April 1955. 



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