Protein Engineering vol. 16 no. 8 pp. 561-575, 2003
© 2003 Oxford University Press
Molecular dynamics simulations of the unfolding of ß2-microglobulin and its variants
1Basic Research Program, SAIC–Frederick, Inc., Laboratory of Experimental and Computational Biology, NCI-FCRDC, Frederick, MD 21702, USA and 2Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
3 To whom correspondence should be addressed. e-mail: ruthn{at}ncifcrf.gov
In this study, we examined the unfolding processes of native ß2-microglobulin and two related variants, one with an N-terminal hexapeptide deletion 
N6 and another with Lys57–Asp58 cleavage, by high-temperature molecular dynamics simulations. Three simulation models were used, molecular dynamics (MD) simulations with explicit water solvation, MD simulations with the CHARMM EEF1 force field and Langevin dynamics with the CHARMM EEF1 force field. Our simulations reproduce many of the experimentally observed structural changes. The most striking agreement is in the ß-strands to 
-helix transition. In our simulations, strands ß3, ß4 and ß5 consistently change to -helix, whereas ß8 changes to an -helix only briefly. Through comparisons of the conformational behavior of the native, the N6 and the Lys-cut ß2-m, using the three simulation methods, we identified the consensus conformational changes that differentiate between the native ß2-m and its two variants. We found that the main effect of the removal of the N-terminal hexapeptide is to increase the separation between strands ß2 and ß6 and to facilitate the ß to transition. On the other hand, the lysine cleavage only increases the flexibility of strand ß5 and does not affect the interactions between strands ß2 and ß6. These conformational changes may relate to polymerization tendencies of these variants.
Received September 18, 2002; revised June 23, 2003; accepted June 25, 2003.