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Protein Design and Evolution.
How do proteins fold? Why are proteins tolerant
to mutations? How did homochirality of the natural amino acids emerge?
These and many other questions arise because we are constantly amazed by
the diversity of function and complexity of structure of proteins and other
biomolecules. An important approach to answering these problems is the
deconstruction of natural proteins by genetic engineering and biophysical
methods, attempting to separate features that contribute to structure,
stability and function. In addition to this, our group uses a bottom-up
approach - trying to design proteins from scratch that recapitulate natural
features.
Chirality: One project in the lab is the
design of peptides and proteins where we deviate from the established
chirality of the 20 ribosomally encoded amino acids. Using computational
methods developed for de novo protein design, we are exploring the
fundamental relationship between chirality and the stability/flexibility
of peptide chains. Additionally, we are developing heterochiral
mini-proteins (HCMPs) that will specifically target protein-protein
interfaces.
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| Fig1:
Mixing L and D - amino acids results increases the number of
possible backbone scaffolds for molecular design (from Nanda &
DeGrado, JACS, 2004). |
Tolerance: A second interest in the lab is
how proteins manage to robustly maintain a folded structure when mutated.
This is clearly an emergent property of proteins that has resulted from the
evolutionary process. We are exploring this feature of proteins by analyzing
the nucleotide sequences of natural proteins evidence of bias to mutational
tolerance. We hope to extend this understanding to the creation of highly
plastic designer proteins that can be easily edited to accommodate new functions.
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| Fig2: There may be evidence
in the nucleotide sequence of proteins for regions that are or are not tolerant to
amino acid change. A metric based on the Plotkin codon-volatility score (Plotkin,
Dushoff and Fraser, Nature, 2004) is being developed to understand the relationship
between mutational tolerance and structure. Above we see two codons for arginine,
one which changes amino acid identity 50% of the time upon single nucleotide
substitution, and the other which changes around 78% of the time. |
Selected Publications
- Nanda V, DeGrado WF. Computational design of heterochiral peptides against a helical target. (2006) J. Am. Chem. Soc. 128, 809-16.
- Nanda V, Rosenblatt MM, Osyczka A, Kono H, Getahun Z, Dutton PL, Saven JG, DeGrado WF. De Novo Design of a Redox-Active Minimal Rubredoxin Mimic. (2005) J. Am. Chem. Soc. 127, 5804-5.
- Nanda V, DeGrado WF. Automated Use of Mutagenesis Data in Structure Prediction. (2005) Proteins: SFB. 59, 454-66.
- Adamian L, Nanda V, DeGrado WF, Liang J. Empirical Lipid Propensities of Amino Acid Residues in Multispan Helical Membrane Proteins. (2005) Proteins: SFB. 59, 496-509.
- Stouffer A, Nanda V, Lear JD, DeGrado WF. Sequence Determinants of a Membrane Proton Channel: An Inverse Relationship Between Stability and Function. (2005) J. Mol. Biol. 347, 169-79.
- Duong-Ly K, Nanda V, DeGrado WF, Howard KP. M2TM Tetramer Conformation Depends on Lipid Bilayer Environment. (2005) Prot. Sci. 14, 856-61.
- Cristian L, Nanda V, Lear JD, DeGrado WF. Synergistic Interactions between Aqueous and Membrane Domains of a Designed Protein Determine its Fold and Stability (2005) J. Mol Biol. 348, 1225-33.
- Nanda V, DeGrado WF. Simulated Evolution of Emergent Chiral Structures in Polyalanine. (2004) J. Am. Chem. Soc. 126, 14459-67.
CABM
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