Crystal molecular dynamics simulations to speed up MM/PB(GB)SA evaluation of binding free energies of di-mannose deoxy analogs with P51G-m4-Cyanovirin-N

J Comput Chem. 2011 Apr 30;32(6):1043-53. doi: 10.1002/jcc.21683. Epub 2010 Oct 14.


Complexes of two Cyanovirin-N (CVN) mutants, m4-CVN and P51G-m4-CVN, with deoxy di-mannose analogs were employed as models to generate conformational ensembles using explicit water Molecular Dynamics (MD) simulations in solution and in crystal environment. The results were utilized for evaluation of binding free energies with the molecular mechanics Poisson-Boltzmann (or Generalized Born) surface area, MM/PB(GB)SA, methods. The calculations provided the ranking of deoxy di-mannose ligands affinity in agreement with available qualitative experimental evidences. This confirms the importance of the hydrogen-bond network between di-mannose 3'- and 4'-hydroxyl groups and the protein binding site B(M) as a basis of the CVN activity as an effective HIV fusion inhibitor. Comparison of binding free energies averaged over snapshots from the solution and crystal simulations showed high promises in the use of the crystal matrix for acceleration of the conformational ensemble generation, the most time consuming step in MM/PB(GB)SA approach. Correlation between energy values based on solution versus crystal ensembles is 0.95 for both MM/PBSA and MM/GBSA methods.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry*
  • Binding Sites
  • Carrier Proteins / chemistry*
  • Crystallization
  • Ligands
  • Mannose / analogs & derivatives
  • Mannose / chemistry*
  • Models, Molecular
  • Molecular Dynamics Simulation*
  • Quantum Theory*
  • Thermodynamics*


  • Bacterial Proteins
  • Carrier Proteins
  • Ligands
  • cyanovirin N
  • Mannose