Destruction of long-range interactions by a single mutation in lysozyme.
We propose a mechanism, based on a > or =10-micros molecular dynamics simulation, for the surprising misfolding of hen egg-white lysozyme caused by a single mutation (W62G). Our simulations of the wild-type and mutant lysozymes in 8 M urea solution at biological temperature (with both pH 2 and 7) reveal that the mutant structure is much less stable than that of the wild type, with the mutant showing larger fluctuations and less native-like contacts. Analysis of local contacts reveals that the Trp-62 residue is the key to a cooperative long-range interaction within the wild type, where it acts like a bridge between two neighboring basic residues. Thus, a native-like cluster or nucleation site can form near these residues in the wild type but not in the mutant. The time evolution of the secondary structure also exhibits a quicker loss of the beta-sheets in the mutant than in the wild type, whereas some of the alpha-helices persist during the entire simulation in both the wild type and the mutant in 8 M urea (even though the tertiary structures are basically all gone). These findings, while supporting the general conclusions of a recent experimental study by Dobson and coworkers [Klein-Seetharam J, Oikama M, Grimshaw SB, Wirmer J, Duchardt E, Ueda T, Imoto T, Smith LJ, Dobson CM, Schwalbe H (2002) Science 295:1719-1722], provide a detailed but different molecular picture of the misfolding mechanism.
Zhou
Ruhong
R
Computational Biology Center, Deep Computing Institute, IBM Watson Research Center, Yorktown Heights, NY 10598, USA. ruhongz@us.ibm.com
Eleftheriou
Maria
M
Royyuru
Ajay K
AK
Berne
Bruce J
BJ
D000595:Amino Acid Sequence; D016000:Cluster Analysis; D003198:Computer Simulation; D003460:Crystallization; D004795:Enzyme Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D011312:Pressure; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity; D013696:Temperature; D014364:Tryptophan / Q000378:metabolism; D014508:Urea / Q000494:pharmacology; D014867:Water / Q000737:chemistry
D014867:Water; D014364:Tryptophan; D014508:Urea; C421864:hen egg lysozyme; D009113:Muramidase