Protein Folding (eBook)

Cláudio M. Gomes is Associate Professor of Biochemistry at the Department of Chemistry and Biochemistry of the Faculty of Sciences (DQB-FCUL), University of Lisbon, where he heads the ‘Protein Folding and Misfolding Laboratory’ within BioISI - Biosystems and Integrative Sciences Institute. He is a Gulbenkian Ph.D. program in Biology and Medicine alumni, and he has obtained is PhD (1999) and Habilitation (2013) in Biochemistry at Universidade Nova de Lisboa. He is an expert on structural biology, biochemistry and biophysics of protein stability, folding and misfolding, with +110 articles published (h-index 26). His current interests focus on mechanisms of protein aggregation in the context of complex biomedical problems such as those arising in Alzheimer’s neurodegeneration. Patrícia F.N. Faísca is Assistant Professor of Physics at the Physics Department of the Faculty of Sciences (DF-FCUL), University of Lisbon, and principal investigator at BioISI – Biosystems and Integrative Sciences Institute. She received her PhD (Physics) in 2002 at the University of Warwick (UK), as part of the Gulbenkian PhD Program in Biology and Medicine. She has a broad interdisciplinary education covering Physics, Biology and Mathematics. Her research on computational biophysics is based on the use of molecular simulations, especially of coarse-grained models. Her current research interests focus on the folding of knotted proteins, and on protein misfolding and aggregation in a disease-related context.

Preface 7
Contents 9
About the Authors 11
1 Protein Folding: An Introduction 12
1 Protein Structure—How Is Structure Maintained? 12
1.1 The Dawn of Protein Structural Biology 12
1.2 The Universe of Protein Structures 13
1.3 Physical Interactions Stabilising Proteins 18
1.4 Protein Dynamics and Solvation 20
2 Protein Folding—Why Is Structure Acquired? 21
2.1 The Anfinsen Experiments 22
2.2 The Thermodynamic Hypothesis 24
2.3 Driving Forces for Protein Folding—Hydrophobic Effect and the Thermodynamics of Protein Folding 25
3 Folding Kinetics and Mechanisms: How Is Structure Acquired? 31
3.1 Two-State Cooperativity in Protein Folding 31
3.2 The Levinthal Paradox and the Timescale of Protein Folding 37
3.3 Mechanisms of Protein Folding 38
3.4 The Nucleation Condensation Mechanism of Protein Folding 39
3.5 Phi-value Analysis and the Structure of the Folding Transition State 39
3.6 The Energy Landscape and Folding Funnels 40
3.7 The Importance of Native Geometry as a Determinant of Folding Rates 42
3.8 The Folding Mechanism of Knotted Proteins 43
4 Protein Misfolding: Why Proteins Misbehave? 45
4.1 Protein Folding In Vivo 45
4.2 Protein Misfolding and Aggregation 49
4.3 Protein Misfolding Diseases 51
4.4 The Amyloid State 52
4.5 Mechanism and Kinetics of Protein Aggregation 56
4.6 Aggregation Propensity 60
5 Methods for Protein Folding 61
5.1 Biophysical Spectroscopies 61
5.2 Computational Methods 64
References 65