From Computer Simulations Meeting Review to Human Disease: Emerging Themes in Protein Folding

United Kingdom Ever since the foundations of protein folding were laidmore than 30 years ago, the importance of bringingUnderstanding how a protein molecule finds its unique togethertheoreticalcalculationsandexperimentalstud-functional three-dimensional structure following its syn- ies has been apparent. Thus, the protein folding fieldthesis on the ribosome is a question that has intrigued was initiated by the inspirational experiments of Anfin-scientists for decades (Anfinsen, 1973). Not only will a sen (who demonstrated that all the information neededsolution to the folding problem complete our knowledge toguideaproteintoitscorrect,biologicallyactivestruc-of the series of events that link a gene sequence and tureishiddenwithinthesequenceofaminoacids[Anfin-the three-dimensional structure of a protein, but it could sen,1973])andthesimple,butthought-provokingcalcu-also play a key role in fine tuning structure prediction lations of Levinthal (1968) (who suggested that foldingalgorithms and open the door to the rational design of occurs along specific pathways rather than by a randomcompletely novel protein molecules. In addition, it is search). In the early 1980s attempts to elucidate foldingnowbecomingclearthatanappreciationofproteinfold- mechanismswereseverelylimitedbythelackofsuitableing has far-reaching consequences in biology, embrac- protein systems for study and the absence of experi-ing topics such as macromolecular recognition, protein mental methods appropriate to the study of a proteintrafficking,theregulationofthecellcycle,diseasessuch as it folds. The limitations of computational methods,as the amyloidoses and cancer, cell invasion, and mem- including the limited quantitative understanding of thebrane fusion. Major progress in understanding protein forces determining molecular interactions (force fields)folding in its widest context is now resulting as a conse- and the lack of the computer power necessary to simu-quence of individuals from a wide range of disciplines late events over a biologically significant timescalejoining forces to address key issues in the field. To this (most small proteins fold in less than a second), alsoend a group of more than 70 scientists recently met ruled out a solution of the folding problem from theoreti-(in December 1998) for a three-day meeting to discuss cal approaches (Karplus, 1997).progress in this endeavor. The meeting was organized Experimentalmethodscapableofmonitoringthefold-by Alan Fersht, Luis Serrano, and Manuel Rico and was ing of proteins in real time began to emerge in the lateheld in the beautiful surroundings of the Instituto Juan 1980s and techniques such as stopped flow circularMarch de Estudios e Investigaciones in Madrid. In this dichroism (which monitors the evolution of secondary