Premium
Thermal unfolding molecular dynamics simulation of Escherichia coli dihydrofolate reductase: Thermal stability of protein domains and unfolding pathway
Author(s) -
Sham Yuk Yin,
Ma Buyong,
Tsai ChungJung,
Nussinov Ruth
Publication year - 2002
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10040
Subject(s) - dihydrofolate reductase , escherichia coli , molecular dynamics , thermal stability , dynamics (music) , escherichia coli proteins , thermal , chemistry , physics , biophysics , thermodynamics , enzyme , biology , biochemistry , computational chemistry , gene , organic chemistry , acoustics
Temperature‐induced unfolding of Escherichia coli dihydrofolate reductase was carried out by using molecular dynamic simulations. The simulations show that the unfolding generally involves an initial end‐to‐end collapse of the adenine binding domain into partially extended loops, followed by a gradual breakdown of the remaining β‐sheet core structure. The core, which consists of β‐strands 5–7, was observed to be the most resistant to thermal unfolding. This region, which is made up of part of the N‐terminus domain and part of the large domain of the E. coli dihydrofolate reductase, may constitute the nucleation site for protein folding and may be important for the eventual formation of both domains. The unfolding of different domains at different stages of the unfolding process suggests that protein domains vary in stability and that the rate at which they unfold can affect the overall outcome of the unfolding pathway. This observation is compared with the recently proposed hierarchical folding model. Finally, the results of the simulation were found to be consistent with a previous experimental study (Frieden, Proc Natl Acad Sci USA 1990;87:4413–4416) which showed that the folding process of E. coli dihydrofolate reductase involves sequential formation of the substrate‐binding sites. Proteins 2002;46:308–320. © 2002 Wiley‐Liss, Inc.