TY - JOUR
T1 - Hydrogen exchange, core modules, and new designed proteins
AU - Carulla, Natàlia
AU - Barany, George
AU - Woodward, Clare
N1 - Funding Information:
This work is supported by NIH grant GM51628.
PY - 2002/12/10
Y1 - 2002/12/10
N2 - A strategy for design of new proteins that mimic folding properties of native proteins is based on peptides modeled on the slow exchange cores of natural proteins. We have synthesized peptides, called core modules, that correspond to the elements of secondary structure that carry the very slowest exchanging amides in a protein. The expectation is that, if soluble in water, core modules will form conformational ensembles that favor native-like structure. Core modules modeled on natural bovine pancreatic trypsin inhibitor have been shown by NMR studies to meet this expectation. The next step toward production of a native state mimic is to further shift the conformational bias of a core module toward more ordered structure by promoting module-module interactions that are mutually stabilizing. For this, two core modules were incorporated into a single molecule by means of a long cross-link. From a panel of several two-module peptides, one very promising lead emerged; it is called BetaCore. BetaCore is monomeric in water and forms a new fold composed of a four-stranded, antiparallel β-sheet. The single, dominant conformation of BetaCore is characterized by various NMR experiments. Here we compare the individual core module to the two-module BetaCore and discuss the progressive stabilization of intramodule structure and the formation of new intermodule interactions.
AB - A strategy for design of new proteins that mimic folding properties of native proteins is based on peptides modeled on the slow exchange cores of natural proteins. We have synthesized peptides, called core modules, that correspond to the elements of secondary structure that carry the very slowest exchanging amides in a protein. The expectation is that, if soluble in water, core modules will form conformational ensembles that favor native-like structure. Core modules modeled on natural bovine pancreatic trypsin inhibitor have been shown by NMR studies to meet this expectation. The next step toward production of a native state mimic is to further shift the conformational bias of a core module toward more ordered structure by promoting module-module interactions that are mutually stabilizing. For this, two core modules were incorporated into a single molecule by means of a long cross-link. From a panel of several two-module peptides, one very promising lead emerged; it is called BetaCore. BetaCore is monomeric in water and forms a new fold composed of a four-stranded, antiparallel β-sheet. The single, dominant conformation of BetaCore is characterized by various NMR experiments. Here we compare the individual core module to the two-module BetaCore and discuss the progressive stabilization of intramodule structure and the formation of new intermodule interactions.
KW - H/D exchange
KW - Protein design
KW - β-sheet protein
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U2 - 10.1016/S0301-4622(02)00149-7
DO - 10.1016/S0301-4622(02)00149-7
M3 - Article
C2 - 12487990
AN - SCOPUS:0037058896
SN - 0301-4622
VL - 101-102
SP - 67
EP - 79
JO - Biophysical Chemistry
JF - Biophysical Chemistry
ER -