Protein Structure and Information Content 117 



IV. CONJECTURES 



Some of the results considered in preparing this paper lead to rather interest- 

 ing speculation. The repetitious minimum entropy polypeptide structures 

 proposed by Pauling, Corey and Branson (8) have already been mentioned. 

 Such configurations may be generally applicable to macromolecules, since 

 helical structures have also been proposed for desoxyribonucleic acid (DNA) 

 polymers (40) and some viruses (41). Crane (42) states that helical configura- 

 tions occur in linear (uni-dimensional) crystals, i.e. structures where progression 

 from each sub-unit to its essentially identical neighbor is by a repeated process 

 of translation and rotation. Lumry and Eyring (43) predict that once hydrogen- 

 bonded secondary structures are formed the characteristic protein 'conformation' 

 is determined by tertiary folding such that the free energy is minimized. How- 

 ever, this does not explain why crystallization should initially occur and be 

 maintained in solution; and to the author's knowledge no one has advanced 

 arguments which provide a complete basis to account for the apparent preval- 

 ence of minimum entropy biostructures, although there have been discussions 

 of how living organisms produce 'order from disorder' or 'order as a result 

 of order' (44). Considering the innumerable configurations available to bio- 

 logical polymers, the question arises 'Are there criteria which determine that 

 the seemingly improbable, highly ordered structures occur spontaneously?' 

 or 'Are these structures imposed at some specific stage in biosynthesis?' 



Studies on the reversible denaturation of proteins (34, 35) suggest that the 

 latter possibihty is more probable: that is, mild mistreatment can be reversed; 

 whereas, once a certain molecular disarray or instability occurs, an unfolded 

 state results from which the characteristic, native structure does not reconstitute. 

 Neurath et al. (35) make the interesting point, that even if denaturation is 

 complete enough so that physical properties such as solubility, crystallizing 

 ability, or diffusion constants are seriously affected, some of the molecules 

 may subsequently revert to a biologically active form; whereas, others will 

 tend to reverse the molecular disarray by forming a more condensed state 

 but without successfully restoring the native biological properties. This suggests 

 that, although polypeptide chains have an inherent tendency to form semi- 

 condensed configurations, the highly ordered, biologically-active structures are 

 probably not only imposed during biosynthesis, but represent quasi-stable 

 structures with built-in constraints which tend to cause small fluctuations 

 to revert, i.e. a limited amount of disorder can be restrained without the inex- 

 orable Second Law prevailing. Neurath (35) has also reported that the amount 

 of disarray compatible with reversibility depends upon the type of denaturation. 

 Further, denaturation is not reversible under all conditions but may await 

 a change in pH or temperature. However, it is interesting that although an 

 entropy increase is invariably associated with denaturation, removal of the 

 denaturing agents can cause a decrease, which appears to contradict the Second 

 Law; we will later resolve this apparent contradiction. 



The quasi-stability of native configurations is suggestive of the situation 

 in diatomic molecules where stability conditions are readily depicted as a 

 local 'weir (relative to the surroundings) or null area in a two-dimensional 

 energy-configuration plot. However, since two dimensions would allow only 



