title: Coarse-grained lattice model simulations of sequence-structure fitness of a ribosome-inactivating protein.
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.
authors.affiliation: Department of Cell Biology and Biochemistry, U.S. Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA. molson@ncifcrf.gov
authors.forename: Mark A
authors.initials: MA
authors.lastname: Olson
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Yeh
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D002151:Calorimetry / Q000379:methods; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D006358:Hot Temperature; D015233:Models, Statistical; D009010:Monte Carlo Method; D015202:Protein Engineering / Q000295:instrumentation / Q000379:methods*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012270:Ribosomes / Q000737:chemistry*; D012276:Ricin / Q000737:chemistry*; D012997:Solvents; D013696:Temperature; D013816:Thermodynamics
chemical_list: D011506:Proteins; D012997:Solvents; D012276:Ricin