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Microsecond MD Simulations of the Plexin-B1 RBD: N-H Probability Density as Descriptor of Structural Dynamics,
Yaron Pshetitsky1, Netanel Mendelman1, Zhenlu Li2
1The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
The Journal of Physical Chemistry. B
|August 18, 2022
Summary
Dimerization significantly alters the flexibility of the Plexin-B1 Rho GTPase binding domain (RBD). Long molecular dynamics simulations reveal differences in flexibility between dimer units, impacting conformational entropy and free energy of dimerization.
Area of Science:
- Computational Biology
- Structural Biology
- Biophysics
Background:
- The Rho GTPase binding domain (RBD) of Plexin-B1 plays a crucial role in cellular signaling.
- Understanding the dynamic structural changes of RBD upon dimerization is essential for elucidating its function.
- Previous studies utilized shorter molecular dynamics (MD) simulations, yielding potentially incomplete insights.
Purpose of the Study:
- To investigate the effect of dimerization on the dynamic structure and conformational entropy of the Plexin-B1 RBD.
- To compare the flexibility of monomeric RBD with its dimeric forms using extended MD simulations.
- To quantify the entropic contribution to the free energy of RBD dimerization.
Main Methods:
- Performed 1 μs all-atom molecular dynamics (MD) simulations of Plexin-B1 RBD in monomeric and dimeric states.
- Derived amide-bond equilibrium probability density functions (P_eq) and conformational entropy (S) from simulation data.
- Analyzed loop and secondary structure element flexibility, comparing monomer and dimer units (d1, d2).
Main Results:
- Dimerization generally increases residue flexibility, with notable differences between dimer units: d1 is unusually flexible, while d2 is rigid, similar to the monomer.
- Specific loops (L1, L3) are consistently flexible, while others (L2, L4) show state-dependent flexibility (L4 flexible in monomer, rigid in dimer).
- The entropy difference between d2 and the monomer contributes -7 ± 0.7 kJ/mol to the free energy of dimerization.
Conclusions:
- Longer MD simulations provide more accurate descriptors of protein structural dynamics and conformational entropy compared to shorter simulations.
- Dimerization induces distinct conformational dynamics in Plexin-B1 RBD units, influencing binding thermodynamics.
- Bond-vector P_eq functions are valuable tools for analyzing protein dynamics and entropy, even with incomplete sampling of slow conformational exchange.
