CONICET | Buscador de Institutos y Recursos Humanos

Abstract. Protein associations, whether transient or long-lasting, determine cellular processes and enable the cooperative and regulated functionalities characteristic of complex organisms. From a broad physical perspective, soluble natural proteins represent a unique kind of solute, prone to associate but not to precipitate. Thus, discrete reproducible associations define the protein supra-molecular organization. The evolutionary forces that enable and promote this complexity are the subject matter of this review. The central problem addressed involves the paradoxical constructive role of random genetic drift, typically mildly deleterious, in fostering interactome complexity. By introducing biophysical insights in molecular evolution we identify the adaptive and non-adaptive elements that define the protein association propensity. We emphasize the mechanistic importance of population size and selection inefficiency in creating an evolutionary niche to promote interactome complexity. Finally, we describe the fitness catastrophes that result from the prevailing evolutionary strategy.