“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 folding problem”. Thus wrote Sir Alan Fehrst, an illustrious scientist from Cambridge, a few years ago. But because, according to another Cambridge scholar, Lord Rutherford : “science is either physics or it is stamp collection”, the “protein folding problem” is also one of the great unsolved problems of physics. This is the reason why the Italian Physical Society organized the present “Enrico Fermi” Summer School, on the premises of Villa Monastero, where Enrico Fermi lectured for the last time in Italy (summer 1954) before his untimely death on November 29th of that year.

It may be stated that the deep connection existing between physics and protein folding is not so much, or in any case not only, through physical methods (experimental: X-rays, NMR, etc, or theoretical: statistical mechanics, spin glasses, etc), but through physical concepts. In particular those associated with the transition of many-body (finite) systems between an initial and a final phase implying breaking of symmetry. In fact, protein folding can be viewed as an emergent property not contained either in the atoms forming the protein or in the forces acting among them, in a similar way as superconductivity emerges as an unexpected coherent phenomenon taking place on a sea of electrons at low temperature.

Let us recall that in spite of the fact that one does not yet know how to read the 3D structure of a protein from its 1D structure, much is known about the protein folding problem, thanks, among other things, to protein engineering experiments (ϕ-values determination, Alan Fehrst and Luis Serrano) as well as from a variety of theoretical inputs: inverse folding problem (Eugene Shakhnovich), funnel-like energy landscapes (Peter Wolynes), helix-coil transitions (Harold Scheraga), etc.

Although quite different in appearance, the fact that the variety of models can account for much of the experimental findings is likely due to the fact that they contain much of the same (right) physics. A physics which is related to the important role played by selected highly conserved, “hot”, amino acids which participate in the stability of independent folding units which, upon docking, give rise to a (post-critical) folding nucleus lying beyond the highest maximum of the free energy associated to the process. In the same way as Heisenberg (matrix) and Schroedinger (differential equation) versions of quantum mechanics have been shown to contain the same physics, it is highly likely that the physics which is at the basis of the different views presented by the lecturers of the phenomenon of protein folding is, to a large extent, equivalent.

This impression also emerged from the answers given by the lecturers to many questions and comments put forward by the lively group of students which attended the School. Within this context, we want to thank them for their attendance and acknowledge the assiduity of their intervents in terms of questions and comments, the high level of the ten minutes talks many of them gave, as well as the high level of the posters presented.

At the basis of their collective response were the high level of the lecturers and seminar speakers presentations. In particular, Harold Scheraga, Peter Wolynes, Eugene Shakhnovich, Amos Maritan, Luis Serrano, Leonid Mirny and Guido Tiana reminded us that while we still do not know how to solve the “protein folding problem”, one has developed a series of powerful methods (like, e.g., chain initiation folding events, foldons and folding funnels, local elementary structures, etc.) which have shed much light on the mechanism which is the basis of the folding of proteins.

It is remarkable that the read thread going through these concepts and corresponding results, starting from those associated with the simplified lattice models discussed by R. A. Broglia, seem to extend all the way to HIV–1 reproduction in infected cell, opening the way for the development of non-conventional (folding) inhibitors, as was reported by Stefano Rusconi, a non-obvious consequence of the in vitro experiments reported by Davide Provasi. A new interdisciplinarity embracing not only physicists, chemists and biologists, but also medical doctors which is likely to be needed to solve such formidable problems as those created by HIV, seems to be in the nascent stage.

The remarkable advances in the field of ab initio studies which has taken place during the last years were reported by Michele Parrinello, Wilfred Van Gunsteren, Paolo Carloni and Peter Winn. Peter Wolynes, Gennady Verkhivker and Giorgio Colombo updated students and lecturers alike on the latest developments on drug design and on the many successes as well as challenges facing this exciting field lying at the borderline between pure and applied research. The role quantum mechanics plays within this context, as well as within the framework of protein folding, was discussed by Kenneth Merz.

The School could have not been possible without the indefatigable support of the President of the Italian Physical Society Professor Franco Bassani, who very early in the programming of the Enrico Fermi School realized the relevance, for physicists, of the subject of protein folding and drug design. To him and to the Secretarial staff (Ramona Brigatti and Giovanna Bianchi Bazzi) headed by Barbara Alzani, as well as to Villa Monastero housekeeper, Antonio Cintorino, our warmest thanks.

Aside from the economical support provided by the Italian Physical Society, we acknowledge the support coming from the University of Milan. The presence in the concluding Session of the School of the Vice President of research Prof. Giampiero Sironi and of the Dean of the Faculty of Sciences, Prof. M. Pignanelli testifies to the importance adscribed by our University to the interdisciplinary field of protein folding and drug design. Within this context, the presence of Prof. Mauro Moroni (Head of the Department of Clinical Sciences, Division of Infective Diseases) and of Prof. Massimo Galli (Director of the Institute of Infective Diseases) of the Faculty of Medicine (and Sacco Hospital), of the University of Milan, was only natural. We also thank the support of INFN (Istituto Nazionale di Fisica Nucleare).

Last, but not least, we acknowledge the privilege of having held this School in the suggestive premises of Villa Monastero, at Varenna, on Como Lake. As one of the lecturers vividly put it, it felt almost surreal to be able to carry out business as usual, namely discuss with each other what we understood, as well as what we do not understand about protein folding, in such beautiful sorroundings.

R. A. Broglia, L. Serrano and G. Tiana