Laboratory of Protein Physics
Organized in 1967 and headed till March, 1999 by Prof. O.B. Ptitsyn (1929-1999). The following groups branched from the laboratory: a Computer Group, a Group of Stereochemistry of Proteins and Nucleic Acids, and a Group of Physical Investigation of Macromolecules (now the Group of Physics of Nucleoproteins).
Main goals: theoretical and experimental investigation of protein folding, including:
The large-scale mobility and changes of protein structures during their functioning (in collaboration with the Group of Nucleoprotein Physics) are also investigated.
1970. The phenomenological (statistical) theory of protein secondary structure has been developed.
1972-1973. A hypothesis has been proposed on the stepwise mechanism of protein 3D structure formation (now commonly called “the framework model”).
1974-1985. The molecular theory of protein secondary structure has been developed and the program package ALB (1982) has been elaborated for automatic prediction of protein and polypeptide secondary structure from their amino acid sequences.
1976-1984. A method has been elaborated for the study of large-scale molecular mobility in proteins by their diffuse X-ray scattering. It was shown that the functioning of some proteins (e.g. phosphoglycerate kinase) is accompanied by the locking and unlocking of their domains.
1978. Abnormal kinetics of b -structure formation has been explained; the developed model can be also applied to the protein behavior in amyloid-like diseases.
1980-1987. A general theory has been developed for the packing of a -helices and b -strands into the compact globule. This theory forms a basis of rational classification of protein structure and reduces the problem of prediction of the protein folding pattern to the choice of the most appropriate folding pattern from their limited set.
1981-1986. The molten globule state, a new physical state of the protein molecule, has been discovered and characterized in details.
1981-1989. The physical nature of protein denaturation has been studied and it has been shown that the first order phase transition upon protein denaturation is connected with the breakdown of the rigid tertiary structure rather than with general unfolding.
1982. A protein engineering technique has been proposed for the “grafting” of a desired active center to impart a new function.
1982-1990. A theory has been elaborated for 3D-structures of random amino acid sequences. On the grounds of this theory a hypothesis has been proposed that real globular proteins are formed from quasi-random amino acid sequences. According to this hypothesis, the evolution of proteins is reduced to the “editing” of such sequences to give a necessary stability of 3D-structure and mainly to create an active center.
1985-1991. A general algorithm has been developed to calculate the free energy of a protein fold and to choose the most appropriate folding pattern for a given sequence.
1987-1991. Investigation of globular protein folding kinetics has shown 3 states in protein folding, one of them is the molten globule-like kinetic intermediate.
1988-1996. The first artificial protein with a new architecture and topology has been constructed and expressed in a cell-free system. The de novo design of this a b protein, albebetin, has been based on the theory of secondary and tertiary structures of a protein molecule. It has been shown that this de novo constructed protein has a stable compact molten globule structure. Albebetin has been modified to carry biological activity corresponding to that of interferon blast-transformation (1993-96).
1988-1999. It has been proposed and experimentally demonstrated that the molten globule state is involved in some physiological process such as the transfer of hydrophobic ligands and interaction with chaperones. It has been shown that the molten globule state can be formed at mild denaturing conditions in the cell.
1991-1995. The quasi-Boltzmann statistics of protein structures have been explained as a consequence of natural selection of stable folds of quasi-random sequences.
1992-1999. The action of errors in energy estimates in protein structure prediction has been studied. Using remote homologs, their common fold can be predicted correctly even when a correct prediction is impossible (due to errors in energy estimates) for all the individual chains.
1992-1999. It has been shown that chaperons GroEL/GroEL do not accelerate protein folding, but only make it more robust and less dependent on the environment of the folding chain. The large scale motions in the GroEL/GroES system have been studied.
1995. A hypothesis has been proposed that the molten globule state is involved in genetic diseases connected with point mutations in some proteins. These mutations can trap protein folding in the kinetic molten globule state.
1996-1999. Two new approaches have been developed to study the nucleation of protein folding:
1997-1999. A new approach has been elaborated to determine distances in a non-native state of a protein molecule using direct energy transfer of tryptophan fluorescence to modified tyrosines. This approach has been applied to measure distances in the molten globule state of apomyoglobin; they coincided with those in the native state. Thus, direct evidence for similarity of structural features of apomyoglobin in both states has been obtained. (Joint work with NCI, NIH, USA).