Molecular Dynamics Simulations of Human Serum Albumin and Role of Disulfide Bonds

Abstract

Atomistic molecular dynamics simulations of human serum albumin in the presence and absence of disulfide bonds are presented. Simulations of 70 ns duration provide information on the relevance of disulfide bonds in the dynamics and structural conformation of HSA. Significant conformational changes are observed in the absence of disulfide bonds after 35 ns that could impact the functionality and stability of the protein. Changes in the secondary structure, hydrogen bonds, B factors, and cross-correlations reveal which disulfide bonds are important for keeping the secondary and tertiary structure and dynamics of the protein (e.g., Cys168-Cys177, Cys278-Cys289) and which have little effect on the local structure and dynamics (e.g., Cys200-Cys246, Cys461-Cys477). Removing all disulfide bonds in the protein appears to be a practical prescreening tool for identifying disulfide bonds relevant to structure and dynamics. In the absence of disulfide bonds, certain hydrogen bonds and correlated motions vanish, affecting the structure of neighboring residues. The structure of the primary binding sites of HSA is partially affected when disulfide bonds are removed. For the native structure, simulations clearly reveal the conformational changes that allow the only free cysteine to be exposed on the protein surface to form intermolecular disulfide bonds; this information could not be resolved from the static crystal structure alone. The absence of specific disulfide bonds could lead to partially unfolded structures; such structures are known to be prone to protein aggregation. Removing disulfide bonds could have similar consequences in other proteins of interest, such as immunoglobulin G.

Allosteric effects of gold nanoparticles on human serum albumin

“…4 shows the RMSDs of Cα atoms of the HSA proteins in the four complexes (100 – 200 ns) and in the bulk solution (0 – 100 ns). The RMSD of the HSA protein in the bulk solution fluctuates from 0.35 to 0.5 nm, consistent with the RMSD fluctuation ranges reported by the Colina group 51 and the Szleifer group 52 in their simulations of an HSA protein in explicit solvent. The RMSDs for the HSA in the four complexes fluctuate in ranges similar to that of the HSA in bulk solution.…”

Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

“…7C and 8C). The most prominent difference was the prevalence of hydrogen bonding between hydrophobic residues Phe 6 , Phe 11 , and Trp 8 in ncSST (Fig. 8C).…”

“…The result shows a peak at ϳ1637 Da corresponding to full-length peptide in the fibril sample suggesting the monomer is resistant to enzyme digestion in the fibrillar state (left); however, it gets degraded in its monomeric state (right). The masses of the digestion products are labeled adjacent to each peak as follows: peak a and peak b in the FIBRIL sample representing a fragment mass of 1277 Da (SST fragment excluding Lys 9 -Thr 10 -Phe 11 ) and 1404 Da (SST fragment excluding Phe 11 -Thr 12 ), respectively. B, aggregation-prediction algorithm Zyggregator suggests almost the entire peptide participates in amyloid formation.…”

Probing the binding site characteristics of HSA: A combined molecular dynamics and cheminformatics investigation

“…warfarin [30], hydroxyquinoline derivatives [31], betulinic acid [32]). More recently Castellanos et al have investigated the role of disulphide bonds on the structural flexibility of the protein [33]. For an extensive review of the most recent molecular modelling studies conducted on HSA please see the following reference [34].…”