PHYSICAL PRINCIPLES OF BIOMOLECULAR RECOGNITION, SELF-ASSEMBLY AND REGULATION

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Interactions between various biological helices control protein folding and assembly, DNA packing, protein-DNA interactions, connective tissue formation and stability, and many other processes responsible for normal function and pathology in living organisms. By combining several experimental techniques (UV-VIS, fluorescence, and FTIR spectroscopy, x-ray diffraction, calorimetry, etc.) with rigorous physical theories, we continued to advance our understanding of these most basic molecular recognition reactions. Our most significant achievements during the past year were: (1) We demonstrated that terminal, non-helical peptides in type I collagen serve as catalytic rather than recognition domains in collagen fibrillogenesis. All information necessary for proper molecular recognition is encoded in the triple helical domain of the protein. (2) We measured molecular interactions in native and reconstituted collagen tissues from mice with osteogenesis imperfecta murine (an analogue of human type III osteogenesis imperfecta). The corresponding mutations lead to formation of type I collagen homotrimers that replace normal heterotrimers. Our studies suggest that these mutations lead to: (a) loss of binding sites for some (still unknown) compound that acts as a molecular glue stabilizing collagen fibers and (b) a reduction in the attractive force responsible for collagen fibrillogenesis and fiber stability. (3) We started investigation of the effect of G349C substitution in a1(I) chain on interaction between type I collagen molecules. Our preliminary data indicate that this mutation (common in human osteogenesis imperfecta) has nosignificant impact by itself. The main source of the observed phenotype manifestations and of the measured changes in collagen-collagen interactions appears to be post-translational protein overmodification, caused by the mutation. (4) We developed a theory of electrostatic interactions between helical macromolecules at all interaxial angles. This theory explains several puzzles of the observed cholesteric phase behavior in DNA aggregates, including the macroscopic pitch of the phase, the cholesteric- nematic transition, and twist sense reversal. - collagen, osteogenesis imperfecta, DNA, spectroscopy, x-ray diffraction, theory