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Molecular dynamics simulations of the unfolding of beta(2)-microglobulin and its variants
1Basic Research Program, SAIC-Frederick, Inc, Laboratory of Experimental and Computational Biology, NCI-FCRDC, Frederick, MD 21702, USA.
Abstract:
In this study, we examined the unfolding processes of native beta(2)-microglobulin and two related variants, one with an N-terminal hexapeptide deletion DeltaN6 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 beta-strands to alpha-helix transition. In our simulations, strands beta(3), beta(4) and beta(5) consistently change to alpha-helix, whereas beta(8) changes to an alpha-helix only briefly. Through comparisons of the conformational behavior of the native, the DeltaN6 and the Lys-cut beta(2)-m, using the three simulation methods, we identified the consensus conformational changes that differentiate between the native beta(2)-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 beta(2) and beta(6) and to facilitate the beta to alpha transition. On the other hand, the lysine cleavage only increases the flexibility of strand beta(5) and does not affect the interactions between strands beta(2) and beta(6). These conformational changes may relate to polymerization tendencies of these variants.
Insights
Molecular dynamics simulations reveal how beta(2)-microglobulin variants unfold. N-terminal deletion facilitates beta-sheet to alpha-helix transitions, while cleavage increases strand flexibility, potentially impacting polymerization.
Area of Science:
- Biophysics
- Computational Biology
- Protein Folding
Background:
- Beta(2)-microglobulin (beta(2)-m) is crucial for immune function.
- Misfolding and aggregation of beta(2)-m are linked to amyloid diseases.
- Understanding beta(2)-m unfolding is key to disease mechanism insights.
Purpose of the Study:
- To investigate the unfolding mechanisms of native beta(2)-microglobulin and two variants.
- To identify conformational differences between native and variant beta(2)-m.
- To correlate structural changes with polymerization tendencies.
Main Methods:
- High-temperature molecular dynamics (MD) simulations.
- Explicit water solvation and CHARMM EEF1 force field.
- Langevin dynamics simulations.
Main Results:
- Simulations accurately reproduced experimentally observed beta-strands to alpha-helix transitions.
- Strands beta(3), beta(4), and beta(5) consistently transitioned to alpha-helices.
- N-terminal hexapeptide deletion increased strand separation and facilitated beta-to-alpha transition.
- Lysine cleavage enhanced beta(5) flexibility but not beta(2)-beta(6) interactions.
Conclusions:
- Distinct conformational changes differentiate native beta(2)-m from its variants.
- N-terminal deletion promotes structural alterations linked to polymerization.
- Lysine cleavage has a more localized effect on beta(5) flexibility.