Protein Folding Overview

Principles

Definition

Protein folding is the academic field concerned with understanding the complex biophysical process by which a linear polypeptide chain acquires its unique, functional three-dimensional structure. This research area investigates the mechanisms, kinetics, thermodynamics, and cellular factors governing this essential process, which is fundamental to protein function and cellular life.

Ontological type

Folding Mechanisms

Energy Landscapes

Folding Kinetics

Key developments

Key Figures

Structural Foundations era

Martin Karplus [1] emerged as a central figure in the Structural Foundations era, with affiliations at Harvard University [3] and the Weizmann Institute of Science [4]. His key contribution during this era is exemplified by Dynamics of folded proteins [6], which connected conformational dynamics to foldability and underscored the role of dynamic constraints in determining native structure. J. Andrew McCammon [2] is associated with Harvard University [3] and Brandeis University [5] during this period. McCammon's work helped catalyze computational approaches to folding dynamics within constrained structural landscapes, as reflected in Dynamics of folded proteins [6], enabling a bridge between structure-driven constraints and kinetic pathways that defined the era.

Energy-Landscape Synthesis era

Peter G. Wolynes [1] is a central figure in the energy-landscape synthesis, with tenure at Rockefeller University [3] and Harvard University [4] during this era. His landmark works The Energy Landscapes and Motions of Proteins [7], Funnels, pathways, and the energy landscape of protein folding: A synthesis [8], and Toward an outline of the topography of a realistic protein-folding funnel [9] helped establish the energy-landscape paradigm and clarified how funnels, pathways, and barrier crossings govern folding thermodynamics and kinetics in this era. Richard A. Friesner [2] is associated with the Massachusetts Institute of Technology [5] and the University of California, San Francisco [6] during this era. His sole era paper Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides [10] advanced protein force fields by refining parameters to better reproduce quantum data, thereby increasing the reliability of computational folding explorations in this energy-landscape framework.

Proteostasis-Integrated Folding era

Robert Tycko [1] is a leading figure in the Proteostasis-Integrated Folding era whose research spans collaborations with institutions such as the University of California, Los Angeles [3] and the University of California, Santa Barbara [4]. His key contribution in this era is the structural elucidation of Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and Phase Separation of Low-Complexity Domains [5], which provided a framework linking intrinsic disorder and phase behavior to folding landscapes. David Eisenberg [2] is a prominent figure in this era whose work is associated with institutions such as the University of California, Los Angeles [3] and the University of California, Santa Barbara [4]. His key contribution includes Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel [6], a finding that advanced understanding of polymorphism and its regulation within cellular proteostasis with implications for misfolding diseases.