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Biopolymers. 2008 Feb;89(2):153-9.

Coarse-grained lattice model simulations of sequence-structure fitness of a ribosome-inactivating protein.

Author information

1
Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. molson@ncifcrf.gov

Abstract

Many realistic protein-engineering design problems extend beyond the computational limits of what is considered practical when applying all-atom molecular-dynamics simulation methods. Lattice models provide computationally robust alternatives, yet most are regarded as too simplistic to accurately capture the details of complex designs. We revisit a coarse-grained lattice simulation model and demonstrate that a multiresolution modeling approach of reconstructing all-atom structures from lattice chains is of sufficient accuracy to resolve the comparability of sequence-structure modifications of the ricin A-chain (RTA) protein fold. For a modeled structure, the unfolding-folding transition temperature was calculated from the heat capacity using either the potential energy from the lattice model or the all-atom CHARMM19 force-field plus a generalized Born solvent approximation. We found, that despite the low-resolution modeling of conformational states, the potential energy functions were capable of detecting the relative change in the thermodynamic transition temperature that distinguishes between a protein design and the native RTA fold in excellent accord with reported experimental studies of thermal denaturation. A discussion is provided of different sequences fitted to the RTA fold and a possible unfolding model.

PMID:
17985366
DOI:
10.1002/bip.20880
[Indexed for MEDLINE]

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