Simulations of Biological Macromolecules

Vaidehi Nagarajan, Wely Floriano, Joyce Peng, Derek Debe, and William Goddard III

Materials and Process Simulation Center,

California Institute of Technology.



In collaboration with Children's hospital at Los Angeles to design inhibitors for the E.coli invasion of the brain microvascular endothelial cells causing meningitis in neonatal infants, we are currently studying the binding determinants of binding N-acetyl glucosamine and its derivatives to the outermembrane protein OmpA. The structure prediction of the membrane proteins using the Restricted Generic Protein(RGP)- Loop Builder for membrane proteins will be discussed in context with OmpA. The preliminary docking studies of two vital ligands chitobiose and fucosyl substituted chitobiose will be presented.

As a part of the ONR-MURI project to understand the mammalian olfactory system we are currently working on the building the tertiary structure model for the olfactory receptors. It is important to understand the nature of binding of the odorants molecules to the odor receptors. There are over 1000 odor receptors in the mammalian systems. We are currently building a suite of programs which would pack the secondary structural elements of the transmembrane proteins (odor recpetors) and build loops for them using Restricted Generic Protein(RGP)- Loop Builder for membrane proteins. Further packing of the helices would be done using Heirarchical NEIMO method(H-NEIMO). An outline of these methods will be discussed. We are currently developing criteria for the recognition of good loop structures using RGP_loop builder for membrane proteins. The merits of the RGP-Loop builder will be discussed. Details relevant to the structure prediction of mor49, an odor receptor would be discussed in the talk by Floriano.

The third part of this talk would be an outline of our study to understand the structure and stability of amyloid fibrils which are relevant in the several neurodegenerative diseases including Huntington's disease and Alzheimer's disease. Formation of the amyloid fibrils have been found to be strongly associated with proteins containing a polyglutamine stretch which is greatly expanded from approximately 20 glutamines in normal individuals to more than 40 in affected individuals. The proteins with longer polyglutamine repeats lead to amyloid fibril formation which results in cell degradation. The amyloids are ordered and stable aggregates and are made up of b sheet structures as the nucleus. Currently we are performing MD simulations on amyloid fibrils using periodic boundary conditions and constant pressure dynamics to understand the stability of the pure polyglutamine amyloid fibrils as compared to the that of Arg substituted polyglutamine. Details of this study would be discussed in talk by Peng.


These projects are funded by NIH-NICHD and ONR-MURI. Some calculations were carried out at the NCSA, Illinois.

full talk HTML