(376ag) Atomistic Insight Toward Dynamic Interactions in Pegylated Bovine Serum Albumin
AIChE Annual Meeting
2019
2019 AIChE Annual Meeting
Computational Molecular Science and Engineering Forum
Poster Session: Computational Molecular Science and Engineering Forum (CoMSEF)
Tuesday, November 12, 2019 - 3:30pm to 5:00pm
The
emergence of biological therapeutics has created higher demand for novel
materials which can improve the stability and activity of native proteins. With
bio-compatible polyethylene glycol (PEG) polymers having been FDA approved for
internal administration within humans, synthesized PEG based bio-conjugates are
increasingly being used to enhance the efficacy of native protein drugs. In this work, ten different initial orientations of the PEG
polymer were generated – prepared by evenly distributing the PEG end-to-end
vector over the accessible protein surface. This methodology was employed to
adequately capture the conformational space, which increases in complexity as a
function of polymer molecular weight, that the grafted PEG chain could sample
around the protein. This methodology enabled us to collect microsecond scale
atomistic molecular dynamics simulation data of PEGylated BSA using PEG
molecular weights of 2, 5, 10 and 20 kDa. Simulations
were conducted with the CHARMM c36m and CHARMM ether forcefields. In addition
to exploring protein-polymer interactions, the effects of the chemical
environment of the conjugated site were studied using N-terminal PEGylated BSA
as well as Lys116 PEGylated BSA. Simulation data from N-terminal conjugated PEG
showed a “shroud”-like wrapped conformation to be favored as the linear PEG
chain molecular weight increases, which is in correlation with experimental
data.1 Calculation of PEG residence time near each residue in
BSA revealed that lysine-PEG interactions play an important role in promoting
PEG-BSA interactions (Figure 1). Due to the unique location of Lys116, results
from Lys116 PEGylated BSA simulations demonstrated how the chemical environment
of the conjugation site can affect dynamics of grafted PEG.
A.; Mathavan, A.; Mathavan,
A.; Lin, P.; Colina, C. M. Molecular Insight into the
Protein–Polymer Interactions in N-Terminal PEGylated Bovine Serum
Albumin. J. Phys. Chem. B 2019
emergence of biological therapeutics has created higher demand for novel
materials which can improve the stability and activity of native proteins. With
bio-compatible polyethylene glycol (PEG) polymers having been FDA approved for
internal administration within humans, synthesized PEG based bio-conjugates are
increasingly being used to enhance the efficacy of native protein drugs. In this work, ten different initial orientations of the PEG
polymer were generated – prepared by evenly distributing the PEG end-to-end
vector over the accessible protein surface. This methodology was employed to
adequately capture the conformational space, which increases in complexity as a
function of polymer molecular weight, that the grafted PEG chain could sample
around the protein. This methodology enabled us to collect microsecond scale
atomistic molecular dynamics simulation data of PEGylated BSA using PEG
molecular weights of 2, 5, 10 and 20 kDa. Simulations
were conducted with the CHARMM c36m and CHARMM ether forcefields. In addition
to exploring protein-polymer interactions, the effects of the chemical
environment of the conjugated site were studied using N-terminal PEGylated BSA
as well as Lys116 PEGylated BSA. Simulation data from N-terminal conjugated PEG
showed a “shroud”-like wrapped conformation to be favored as the linear PEG
chain molecular weight increases, which is in correlation with experimental
data.1 Calculation of PEG residence time near each residue in
BSA revealed that lysine-PEG interactions play an important role in promoting
PEG-BSA interactions (Figure 1). Due to the unique location of Lys116, results
from Lys116 PEGylated BSA simulations demonstrated how the chemical environment
of the conjugation site can affect dynamics of grafted PEG.
Figure 1: Representation of loop-like conformation formed by PEG
near lysine residues in a 10 kDa PEGylated system
when forming a "shroud" like conformation around BSA. Hydrogen atoms
are not shown for clarity. Surrounding residues near each lysine are colored in
yellow (hydrophobic) and green (all others).
A.; Mathavan, A.; Mathavan,
A.; Lin, P.; Colina, C. M. Molecular Insight into the
Protein–Polymer Interactions in N-Terminal PEGylated Bovine Serum
Albumin. J. Phys. Chem. B 2019