Cambridge mathematician and Harvard philosopher Alfred North Whitehead provided excellent advice for scientists. He said, “Seek simplicity but distrust it” (1Whitehead A.N. Russell B. 2nd Ed. Principia Mathematica. Vol. III. Cambridge University Press, New York1963Google Scholar). Scientists who like to explain observed phenomena by reduction, and to model experimental results using (mostly mechanical) models, often follow the first part of Whitehead’s sentence while forgetting the second. For describing the thermodynamic and phase-equilibrium properties of globular-protein solutions, it has been customary to model the protein as a hard sphere bearing an electric charge that depends on the solution’s pH. The charged sphere interacts with other spheres through electrostatic and (London) dispersion forces in a continuous dielectric medium that may contain other globular solutes as well as salt at known ionic strength. Using the concept potential of mean force coupled with hard-sphere perturbation theory, it is then possible to calculate the phase diagram where temperature is plotted against the number density of protein particles in the solution, as shown in Fig. 1. This procedure is similar to the more than 60-year-old DVLO theory for describing the thermodynamic properties of colloid solubilities. Upon making some structural assumptions about globular-protein crystals, it is also possible to calculate liquid-solid as well as liquid-liquid equilibria for protein solutions (2Mahadevan H. Hall C.K. Statistical-mechanical model of protein precipitation by nonionic polymer.J. Am. Inst. Chem. Eng. 1990; 36: 1517Crossref Scopus (88) Google Scholar). Numerous publications along these lines have appeared in the literature, although comparisons with experiment are rare (2Mahadevan H. Hall C.K. Statistical-mechanical model of protein precipitation by nonionic polymer.J. Am. Inst. Chem. 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Analytic calculation of phase diagrams for solutions containing colloids or globular proteins.Colloid Polym. Sci. 2004; 282: 620-632Crossref Scopus (41) Google Scholar). Authors of the extensive literature on the theory of protein solutions have not been inhibited by the many (often drastic) simplifications required to obtain a simple result, perhaps relying on J. H. Hildebrand’s remark (J. H. Hildebrand, University of California, Berkeley, personal communication, 1979) that, when trying to establish a simple theory for a complex phenomenon, it is better to make many, rather than a few, simplifying assumptions because there is a good chance that the errors from some assumptions will be canceled by the errors from some other assumptions. Hildebrand’s remark (J. H. Hildebrand, University of California, Berkeley, personal communication, 1979), coupled with the first part of Whitehead’s advice (1Whitehead A.N. Russell B. 2nd Ed. Principia Mathematica. Vol. III. Cambridge University Press, New York1963Google Scholar), provide music to the ears of those applied scientists (like me) who want an easy solution to a complex problem. Of course applied scientists know that, in principle, calculations based on colloidal behavior are not really valid for protein solutions and that one should not confuse globular proteins with perturbed hard spheres, as stated in Whitehead’s fallacy of misplaced concreteness, where results from a model are erroneously believed equivalent to reality. Although we may not want to admit it, deep-down we know that the perturbed-hard-sphere theory is not correct for representing the properties of a protein solution. It’s bad, yes, but how bad? Little attention has been given to this question until the pioneering work of Sarangapani et al. (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar) published in this issue of the Biophysical Journal. Sarangapani et al. (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar) have performed extensive experimental studies of bovine serum albumin (BSA) solutions as a function of pH, ionic strength, and protein concentration at several temperatures. Experimental studies include rheology, neutron scattering, and ultraviolet circular dichroism. These studies, coupled with extensive published data for BSA, show that models based on colloidlike assumptions are in serious error. The authors conclude that proteins are not simple particles of fixed dimension; they are polyelectrolytes whose configurations change with solution conditions, especially with protein concentration. The potential of mean force depends strongly on protein concentration due to changes in the protein’s tertiary structure. The authors present convincing evidence (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar) that “The idealized view in the literature that proteins such as BSA are rigid ellipsoidal colloidal particles, whose size and shape are invariant with protein concentration and pH, is found to be untenable.” Protein particles in solution are much more complex than hard spheres in solution even when the properties of hard sphere are adjusted (perturbed) by addition of a variety of interparticle attractive and repulsive forces. Unlike hard spheres, protein particles change size, shape, and extension as solution conditions vary. In an initial effort toward improved understanding, the authors discuss a more realistic interpretation of scattering data than that provided by the conventional method based on colloidlike behavior. To obtain a better understanding of BSA properties in solution, the authors suggest molecular-dynamic simulations. Many (like me) will be secretly unhappy about the demise of the colloidlike theory of globular-protein solutions. Although we knew that this theory was “sick”, we hoped that it might “recover”. But now, after the report of Sarangapani et al. (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar), the colloidlike theory is dead; the Sarangapani group have delivered a coup de grâce. We can take comfort in the remark of Sarangapani et al. (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar) that, while scientifically erroneous, the colloidlike theory may nevertheless be useful for some purposes in biotechnology. Thank you! That’s like saying even a placebo can sometimes cure an illness. While we mourn with sadness, we also owe much thanks to Sarangapani et al. (12Sarangapani P.S. Hudson S.D. Pathak J.A. Critical examination of the colloidal particle model of globular proteins.Biophys. J. 2014; 108: 724-737Abstract Full Text Full Text PDF Scopus (64) Google Scholar) for reminding us that, when describing nature, yes, by all means seek simplicity but, with respect for complexity, don’t forget to mistrust it. Critical Examination of the Colloidal Particle Model of Globular ProteinsSarangapani et al.Biophysical JournalFebruary 03, 2015In BriefRecent studies of globular protein solutions have uniformly adopted a colloidal view of proteins as particles, a perspective that neglects the polymeric primary structure of these biological macromolecules, their intrinsic flexibility, and their ability to sample a large configurational space. While the colloidal perspective often serves as a useful idealization in many cases, the macromolecular identity of proteins must reveal itself under thermodynamic conditions in which the native state is no longer stable, such as denaturing solvents and high protein concentrations where macromolecules tend to have screened excluded volume, charge, and hydrodynamic interactions. Full-Text PDF Open Archive