Local Structures in Proteins from Microsecond Molecular Dynamics Simulations: A Symmetry-Based Perspective

Yaron Pshetitsky, Netanel Mendelman, Matthias Buck, Eva Meirovitch

Research output: Contribution to journalArticlepeer-review


We report on a new method for the characterization of local structures in proteins based on extensive molecular dynamics (MD) simulations, here, 1 μs in length. The N-H bond of the Rho GTPase binding domain of plexin-B1 (RBD) serves as a probe and the potential, u(MD), which restricts its internal motion, as a qualifier of the local dynamic structure. u(MD) is derived from the MD trajectory as a function of the polar angles, (θ, φ), which specify the N-H orientation in the protein. u(MD) is statistical in character yielding empirical descriptions. To establish more insightful methodical descriptions, we develop a comprehensive method which approximates u(MD) by combinations of analytical Wigner functions that belong to the D2h point group. These combinations, called u(simulated), make it possible to gain a new perspective of local dynamic structures in proteins based on explicit potentials/free energy surfaces and associated probability densities, entropy, and ordering. A simpler method was developed previously using 100 ns MD simulations. In that case, the traditional “perpendicular N-H ordering” setting centered at Cα-Cα with (θ, φ) = (90, 90) and generally, featuring positive φ, prevailed. u(MD) derived from 1 μs MD simulations is considerably more complex requiring substantial model enhancement. The enhanced method applies to the well-structured sections of the RBD. It only applies partly to its loops where u(MD) extends into the negative-φ region where we detect nonperpendicular N-H ordering. This arrangement requires devising new reference structures and making substantial algorithmic changes, to be performed in future work. Here, we focus on developing the comprehensive method and using it to investigate perpendicular ordering settings. We find that secondary structures (loops) exhibit varying (virtually invariant) potentials with Ag, B2u, and B1u (Ag and B2u) D2h symmetry. Application to RBD dimerization and RBD binding to the GTPase Rac1 is described in the subsequent article. Applications to other probes, proteins, and biological functions, based on explicit local potentials, probability densities, entropy, and ordering, are possible.

Original languageEnglish
Pages (from-to)1557-1572
Number of pages16
JournalJournal of Physical Chemistry B
Issue number7
StatePublished - 22 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 American Chemical Society.


We acknowledge support from the Israel Science Foundation (grant 288/20 to E.M.) and the Binational Israel-U.S.A. Science Foundation (grant 2016097 to E.M. and Jack H. Freed). The work of M.B. for this project was supported by the NIH grants R01GM112491 and R01EY029169.

FundersFunder number
National Institutes of HealthR01GM112491, R01EY029169
United States-Israel Binational Science Foundation2016097
Israel Science Foundation288/20


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