Ebook: Protein Folding, Evolution and Design

Proteins are the major functional molecules of life. They have evolved through selection pressure to perform specific functions. The functional properties of proteins depend upon their three-dimensional structures. One of the great unsolved problems of science is the prediction of the three-dimensional structure of a protein from its amino acid sequence.

The CXLV Course of the International School of Physics “Enrico Fermi” brought together scientists from a variety of areas of protein science and of physics. It provided a unique oportunity for discussions across the borders, at a time in which physicists addicted to simplifications are beginning to learn how much small details can matter in describing the properties of proteins, and molecular biologists are starting to appreciate the usefulness of having numbers attached to arrows of their cartoons and equations relating the numbers.

During the School the subject of protein folding and of protein design and evolution were discussed, both experimentally (W. Eaton, D. Eisenberg, A. Fersht, L. Serrano, V. Goldanskii and M. Oliveberg) and theoretically (R. A. Broglia, A. Finkelstein, A. Maritan, L. Mirny, H. Orland E. Shakhnovich, G. Tiana), as well as their connection to the general subject of polymers and of spin glasses (A. Grosberg, A. Khokhlov, G. Parisi). The audience made out of an extremely gifted group of young students and practitioners, contributed in a very active fashion to the School not only through questions and discussions, but also through the presentation of short, highly articulated seminars, touching on subjects lying at the forefront of protein research.

The lectures started with a review of the field and a discussion of the latest experimental progress in the subject of protein engineering and of protein design by Alan Fersht and Luis Serrano, respectively. Their lectures were central to the School, but are the only ones missing from the Proceedings. If one should look for a reason for this fact, one is reminded that Alan, at the time of the conference, had just published the third edition of his authorative monography Structure and Mechanism in Protein Science (W. H. Freeman Co., New York), while Luis was helping at creating a start-up biomedical venture. It is not easy to write a synthesis of a masterpiece, nor to have much time left over for relaxed writing when one goes private. While these facts did not make any easier the life of the editors of the present Proceedings, they reflect the vitality and breadth of interests the subject of protein folding and design has awaken in the scientific comunity.

On behalf of all the participants to the course we would like to express our gratitude to the Italian Physical Society for providing hospitality in the exquisite setting of Villa Monastero. We want also to thank several funding agencies (NATO, European Union, Unesco) for providing the funds needed to make the whole project a reality.

In the organization of the course it has been a great pleasure to work with Prof. F. Bassani, President of the Italian Physical Society. We would also like to express our thanks to Dr. G. Tiana, who acted as Scientific Secretary of the course, and to pay tribute to the kindness and efficiency of the secretarial staff headed by C. Vasini and B. Alzani.

R. A. Broglia and E. I. Shakhnovich

1. Basic idea of the experiment

2. Quenching probability and diffusion-limited rate

3. Length dependence of end-to-end contact rate

4. Mean-squared end-to-end distance and end-to-end diffusion constant

5. Concluding remarks

1. What is the folding transition state?

2. The gross behaviour of the transition state and the parameter β‡

3. Phi-value analysis

4. Transition state shifts and the broad barrier model

5. From snap-shot to movie: scanning the activation barrier by a moving transition state

6. Determining the folding pathway directly from the native structures

1. Introduction

2. Experimental part

3. Summary and discussion

1. Introduction

2. Basic concepts

3. Simple lattice and topology-based models

4. Evolutionary studies

5. Molecular dynamics: folding pathways inferred from unfolding simulations

6. All-atom Monte Carlo simulations: possible folding mechanism at an atomic level of detail

7. Concluding remarks

1. Introduction

2. The model

3. How does a notional protein fold?

4. Predicting the 3D structure of a notional protein from its amino acid sequence

5. Conclusions and perspectives

1. Introduction

2. The HP Model

3. The twenty-letter model

4. Designability of different conformations

5. Conclusions

1. Introduction

2. Rouse model

3. Including interactions

4. Conclusion

1. Scope of the lectures

2. Introduction

3. Optimal shape of a compact polymeric chain

4. Fast-folding polymers and role of secondary motifs

5. Density of overlapping conformations for protein structures and role of natice-state topology in the folding process

6. Application of geometrical models to investigate the folding membrane proteins

1. Introduction

2. Simulation method

3. Results

4. Discussion

1. Introduction

2. Methods

3. Results

4. Discussion

1. Introduction

2. Principles of molecular evolution

3. Applications to proteins

4. Conclusion

1. Introduction

2. DNA's point of view

3. Proteins' point of view

1. Introduction

2. Methods

3. Two models

4. Results

5. Conclusion

6. The maximal value of the sequence entropy

1. Introduction

2. Glassiness and metastability

3. General considerations on the coexistence of many phases

4. The overlap and its probability distribution

5. Off-equilibrium dynamics

6. The inherent structure picture for glasses

7. The form of the free-energy landscape

8. Some analytic and numerical results

9. Conclusions

1. Introduction

2. Entropy and geometry of compact conformations: Flory theorem, or what is secondary structure?

3. Entropy and geometry of conformation space

4. Entropy and geometry in sequence space

1. Introduction. Bio-evolution mimetics

2. Protein-like AB-copolymers: computer generation and properties of the coil-globule transition

3. Long-range correlations in protein-like AB-copolymers

4. AB-copolymers which mimic membrane proteins

5. ABC-copolymers modeling proteins with active enzymatic center

6. Adsorption-tuned AB-copolymers

7. Conclusions