Mechanisms of Protein Assembly:  Lessons from Minimalist Models

Yaakov Levy received his Ph.D. from Tel-Aviv University, Israel, in 2002. He is currently a postdoctoral researcher in the groups of Profs. José Onuchic and Peter Wolynes at the University of California at San Diego. He will soon join the Department of Structural Biology at the Weizmann Institute as a Senior Lecturer. His current research interests focus on understanding the first principles of biological self-organization processes using theoretical and computational tools.

José Onuchic received his Ph.D. from Caltech in 1987. He joined the faculty of the University of California at San Diego in 1990, where he is currently Professor in Physics and co-director of the Center for Theoretical Biological Physics. His current research interests center on theoretical and computational methods for molecular biophysics and chemical reactions in condensed matter, with special emphasis in protein folding and electron transfer in biomolecules.

Many cellular functions rely on interactions among proteins and between proteins and nucleic acids. The limited success of binding predictions may suggest that the physical and chemical principles of protein binding have to be revisited to correctly capture the essence of protein recognition. In this Account, we discuss the power of reduced models to study the physics of protein assembly. Since energetic frustration is sufficiently small, native topology-based models, which correspond to perfectly unfrustrated energy landscapes, have shown that binding mechanisms are robust and governed primarily by the protein's native topology. These models impressively capture many of the binding characteristics found in experiments and highlight the fundamental role of flexibility in binding. The essential role of solvent molecules and electrostatic interactions in binding is also discussed. Despite the success of the minimally frustrated models to describe the dynamics and mechanisms of binding, the actual degree of frustration has to be explored to quantify the capacity of a protein to bind specifically to other proteins. We have found that introducing mutations can significantly reduce specificity by introducing an additional binding mode. Deciphering and quantifying the key ingredients for biological self-assembly is invaluable to reading out genomic sequences and understanding cellular interaction networks.