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Molecular dynamics simulation of Escherichia coli dihydrofolate reductase and its protein fragments: Relative stabilities in experiment and simulations
Author(s) -
Sham Yuk Yin,
Ma Buyong,
Tsai ChungJung,
Nussinov Ruth
Publication year - 2001
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.33301
Subject(s) - dihydrofolate reductase , molecular dynamics , escherichia coli , folding (dsp implementation) , protein folding , protein structure , chemistry , protein secondary structure , fragment (logic) , crystallography , beta sheet , native state , beta (programming language) , reductase , biophysics , biology , enzyme , biochemistry , computational chemistry , algorithm , mathematics , programming language , computer science , electrical engineering , gene , engineering
We have carried out molecular dynamics simulations of the native dihydrofolate reductase from Escherichia coli and several of its folded protein fragments at standard temperature. The simulations have shown fragments 1–36, 37–88, and 89–159 to be unstable, with a C α RMSD (C α root mean squared deviation) >5 Å after 3.0 nsec of simulation. The unfolding of fragment 1–36 was immediate, whereas fragments 37–88 and 89–159 gradually unfolded because of the presence of the β‐sheet core structure. In the absence of residues 1–36, the two distinct domains comprising fragment 39–159 associated with each other, resulting in a stable conformation. This conformation retained most of its native structural elements. We have further simulated fragments derived from computational protein cutting. These were also found to be unstable, with the exception of fragment 104–159. In the absence of α 4 , the loose loop region of residues 120–127 exhibited a β‐strand‐like behavior, associating itself with the β‐sheet core of the protein fragment. The current study suggests that the folding of dihydrofolate reductase involves cooperative folding of distinct domains which otherwise would have been unstable as independent folded units in solution. Finally, the critical role of residues 1–36 in allowing the two distinct domains of fragment 104–159 to fold into the final native conformation is discussed.