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Molecular dynamics simulations of a hydrated protein vectorially oriented on polar and nonpolar soft surfaces.

ABSTRACT: We present a collection of molecular dynamics computer simulation studies on a model protein-membrane system, namely a cytochrome c monolayer attached to an organic self-assembled monolayer (SAM). Modifications of the system are explored, including the polarity of the SAM endgroups, the amount of water present for hydration, and the coordination number of the heme iron atom. Various structural parameters are measured, e.g., the protein radius of gyration and eccentricity, the deviation of the protein backbone from the x-ray crystal structure, the orientation of the protein relative to the SAM surface, and the profile structures of the SAM, protein, and water. The polar SAM appears to interact more strongly with the protein than does the nonpolar SAM. Increased hydration of the system tends to reduce the effects of other parameters. The choice of iron coordination model has a significant effect on the protein structure and the heme orientation. The overall protein structure is largely conserved, except at each end of the sequence and in one loop region. The SAM structure is only perturbed in the region of its direct contact with the protein. Our calculations are in reasonably good agreement with experimental measurements (polarized optical absorption/emission spectroscopy, x-ray interferometry, and neutron interferometry).

SUBMITTER: Nordgren CE

PROVIDER: S-EPMC1302375 | biostudies-other | 2002 Dec

REPOSITORIES: biostudies-other

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Molecular dynamics simulations of a hydrated protein vectorially oriented on polar and nonpolar soft surfaces.

Nordgren C E CE Tobias D J DJ Klein M L ML Blasie J K JK

Biophysical journal 20021201 6

We present a collection of molecular dynamics computer simulation studies on a model protein-membrane system, namely a cytochrome c monolayer attached to an organic self-assembled monolayer (SAM). Modifications of the system are explored, including the polarity of the SAM endgroups, the amount of water present for hydration, and the coordination number of the heme iron atom. Various structural parameters are measured, e.g., the protein radius of gyration and eccentricity, the deviation of the pr ...[more]

PMID: 12496067

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Project description:Understanding how making structural changes in small molecules affects their binding affinities for targeted proteins is central to improving strategies for rational drug design. To assess the effects of varying the nature of nonpolar groups upon binding entropies and enthalpies, we designed and prepared a set of Grb2-SH2 domain ligands, Ac-pTyr-Ac6c-Asn-(CH2)n-R, in which the size and electrostatic nature of R groups at the pTyr+3 site were varied. The complexes of these ligands with the Grb2-SH2 domain were evaluated in a series of studies in which the binding thermodynamics were determined using isothermal titration calorimetry, and binding interactions were examined in crystallographic studies of two different complexes. Notably, adding nonpolar groups to the pTyr+3 site leads to higher binding affinities, but the magnitude and energetic origins of these effects vary with the nature of the R substituent. For example, enhancements to binding affinities using aliphatic R groups are driven by more favorable changes in binding entropies, whereas aryl R groups improve binding free energies through a combination of more favorable changes in binding enthalpies and entropies. However, enthalpy/entropy compensation plays a significant role in these associations and mitigates against any significant variation in binding free energies, which vary by only 0.8 kcal•mol-1, with changes in the electrostatic nature and size of the R group. Crystallographic studies show that differences in ΔG° or ΔH° correlate with buried nonpolar surface area, but they do not correlate with the total number of polar or van der Waals contacts. The relative number of ordered water molecules and relative order in the side chains at pTyr+3 correlate with differences in -TΔS°. Overall, these studies show that burial of nonpolar surface can lead to enhanced binding affinities arising from dominating entropy- or enthalpy-driven hydrophobic effects, depending upon the electrostatic nature of the apolar R group.

Dataset Information

Molecular dynamics simulations of a hydrated protein vectorially oriented on polar and nonpolar soft surfaces.

Publications

Molecular dynamics simulations of a hydrated protein vectorially oriented on polar and nonpolar soft surfaces.

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