Theory and computational modeling are vibrant components of Biophysics at Michigan. As biology advances into this century, new levels of quantitative understanding of biological systems are emerging from the strong partnership between theory/modeling and experiment. At Michigan, Theoretical and Computational Biophysicists are at the forefront of developing and using theoretical approaches to extend our understanding of biological processes associated with protein and nucleic acid structure, folding, misfolding and assembly, drug discovery and design and cellular processing.
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Using novel methods to incorporate pH directly into molecular simulation studies, Brooks’ group has explored the role pH plays in the formation of amyloid fibrils in peptides from Alzheimer’s Aβ peptide. Their findings demonstrate that in low and high pH environments an increased propensity for the peptide to adopt helical conformations acts to “protect” the peptide from forming oligomers, as precursors to amyloid formation. However, at intermediate values of pH, such as those found in early endosomes, pH ~ 6, conformations revealing the maximal exposure of the central hydrophobic core of the Aβ peptide supports the formation of oligomers that could ultimately lead to amyloid fibrils or larger oligomeric states that may be involved in the Alzheimer pathology. The structures shown represent the centroids of the most populated conformational clusters observed in molecular dynamics simulations carried out at the indicated pH values. At pH=6 the central hydrophobic core is displayed in a van der Waals representation. The putative dimer structure is meant to be suggestive of formation of early oligomers and is a hypothetical structure for purposes of illustration. The figure was adapted from Khandogin & Brooks, Proc Natl Acad Sci, USA, 104: 16880 (2007).
