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Abstract
Sickle cell disease (SCD) is an autosomal recessive inherited disorder associated with a single substitution (Glu-beta6→Val-beta6) in the -globins of the hemoglobin molecule. This replacement induces the aggregation of deoxygenated sickle cell hemoglobin (deoxy-HbS) into helical fibers that distort the red blood cells into a rigid sickle-like shape. Despite advances in stem cell and gene therapy as well as the recent approval of a new anti-sickling drug, therapeutic limitations subsist. Herein, we investigate, through molecular dynamics (MD), the effect of nine 5-mer cyclic peptides (CPs), tailor-designed to bind to the hydrophobic pocket or its surroundings, involved in key lateral contacts of HbS fibers. The size of the CPs was chosen to minimize proteolysis and favor cell penetration, while still allowing blocking the abovementioned region. Our results show that the CPs bind to the HbS pocket, orthogonally to the surface of the protein, with some revealing exceedingly long residence times. These CPs display a moderate to high specificity, exhibiting molecular recognition events in unbiased simulations, even at a HbS:CP (1:1) ratio. Further, hydration and binding free energies from alchemical and umbrella sampling MD indicate that all CPs should be soluble, although hydrophobic peptides are slightly self-aggregation prone. The respective CP-CP dimerization free energy is, nevertheless, higher (by a factor of ~ 6) than the HbS-CP binding free energy. A much lower (by a factor of ~ 6) HbS-CP binding free energy, longer residence times, and higher specificity are also found relative to a previously reported CP with modest in vitro antisickling activity. These results indicate that some of the CPs designed herein, namely, VVVVV and VFVFV (neutral), VEVFV (charge -1), VEVEV (charge -2), and VKVKV (charge +2) have the potential to reduce the concentration of aggregation-competent deoxy-HbS, by blocking or delaying the formation of the lateral contact at the homogeneous nucleation and/or fiber growth stages.
Supplementary materials
Title
Supporting Information
Description
Table 1 – Density, self-diffusion, and shear viscosity of the mTIP3P and TIP3P water models at 298 K and 0.1 MPas.
Figure S1 – RMSD and secondary structure of the CHARMM36 HbS model with the mTIP3P and TIP3P water models.
Figure S2 – Moving average of the minimum distance between the CP VVVVV and the HbS pocket in the HbS:CP (1:1) system, with the mTIP3P and TIP3P water models.
Figure S3 – Moving averages of the minimum distance between some CPs and the HbS pocket, up to 500 ns.
Figure S4 – Solvent accessible surface area (SASA) of the hydrophobic pocket involved in the lateral contact of HbS fibers.
Figure S5 - Normalized HbS-CP contact maps for the HbS:CP (1:1) systems for a Rmin < 4.5 Å protein-CP contact definition.
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