Abstract：
:Membrane-bound protein receptors are a primary biological drug target, but the computational analysis of membrane proteins has been limited. In order to improve molecular mechanics Poisson-Boltzmann surface area (MMPBSA) binding free energy calculations for membrane protein-ligand systems, we have optimized a new heterogeneous dielectric implicit membrane model, with respect to free energy simulations in explicit membrane and explicit water, and implemented it into the Amber software suite. This new model supersedes our previous uniform, single dielectric implicit membrane model by allowing the dielectric constant to vary with depth within the membrane. We calculated MMPBSA binding free energies for the human purinergic platelet receptor (P2Y12R) and two of the muscarinic acetylcholine receptors (M2R and M3R) bound to various antagonist ligands using both membrane models, and we found that the heterogeneous dielectric membrane model has a stronger correlation with experimental binding affinities compared to the older model under otherwise identical conditions. This improved membrane model increases the utility of MMPBSA calculations for the rational design and improvement of future drug candidates.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Greene D,Qi R,Nguyen R,Qiu T,Luo Rdoi
10.1021/acs.jcim.9b00363subject
Has Abstractpub_date
2019-06-24 00:00:00pages
3041-3056issue
6eissn
1549-9596issn
1549-960Xjournal_volume
59pub_type
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