Effect of Protein Flexibility from Coarse-Grained Elastic Network Parameterizations
on the Calculation of Free Energy Profiles of Ligand Binding
Posted on 2020-06-18 - 07:14
The
characterization of the affinity and binding mechanism of specific
molecules to a protein active site is scientifically and industrially
relevant for many applications. In principle, this information can
be obtained using molecular dynamics (MD) simulations by calculating
the free energy profile of the process. However, this is a computationally
demanding calculation. Currently, coarse-grained (CG) force fields
are very well implemented for MD simulations of biomolecular systems.
These computationally efficient force fields are a major advantage
to the study of large model systems and/or those requiring long simulation
times. The Martini model is currently one of the most popular CG force
fields for these systems. For the specific case of protein simulations,
to correctly maintain the macromolecular three-dimensional structure,
the Martini model needs to include an elastic network (EN). In this
work, the effect of protein flexibility, as induced by three EN models
compatible with the Martini force field, was tested on the calculation
of free energy profiles for protein-ligand binding. The EN models
used were ElNeDyn, GoMartini, and GEN. The binding of triolein (TOG)
and triacetin (TAG) to a lipase protein (thermomyces lanuginosa lipase-TLL) was used as a case study. The results show that inclusion
of greater flexibility in the CG parameterization of proteins is of
high importance in the calculation of the free energy profiles of
protein-ligand systems. However, care must be taken in order to avoid
unjustified large protein deformations. In addition, due to molecular
flexibility there may be no absolute need for the center of the ligand
to reach the center of the protein-binding site. The calculation of
the energy profile to a distance of about 0.5 nm from the active site
center can be sufficient to differentiate the affinity of different
ligands to a protein.
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Filipe, Hugo A. L.; Esteves, Margarida I. M.; Henriques, César A.; Antunes, Filipe E. (2020). Effect of Protein Flexibility from Coarse-Grained Elastic Network Parameterizations
on the Calculation of Free Energy Profiles of Ligand Binding. ACS Publications. Collection. https://doi.org/10.1021/acs.jctc.0c00418
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AUTHORS (4)
HF
Hugo A. L. Filipe
ME
Margarida I. M. Esteves
CH
César A. Henriques
FA
Filipe E. Antunes