Analyzing PEGylation through Molecular Dynamics Simulations

Abstract

Poly(ethylene) glycol (PEG) is the most used polymer in drug delivery due to its unique properties, such as reduced toxicity and high solubility. PEGylation is the process of attaching PEG chains to compounds. Its effect on drug delivery has motivated a lot of experimental and computational studies. To explain and complement experimental findings, all-atom, coarsegrained and multi-scale molecular dynamics simulations are being increasingly done. This review summarizes the computational studies using molecular dynamics that have been done regarding PEG and PEGylation of small molecules, proteins, peptides and drug nanocarriers such as micelles, liposomes, dendrimers and carbon nanotubes. Generally, the various studies presented indicate that molecular dynamics simulations can be a powerful tool in explaining and predicting experimental results and are efficient in providing an atomic-level insight into the interactions between PEG molecules and other compounds. In particular, MD simulations are nowadays routinely used to provide direct insight into the dominant conformations formed, range of interactions established, and effect of PEGylation on the structural and dynamic properties of different drugs or therapeutic agents, enabling an atomic level analysis of a variety aspects including ionic concentration, identify of ions present, and specific PEG size and number of molecules. Figure 1. Types of PEG chains. X represents functional groups and n represents the number of individual units in the chain. In multi-arm PEG chains oxygen atoms were omitted for clarity.

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

“…Note that the conformation of PEGs and their interactions with other molecules can be reasonably predicted only in the presence of accurate FFs. For the development of all-atom [15][16][17][18][19][20][21][22][23] and CG models [24][25][26][27][28][29][30][31] for PEG and PEO, previous review papers are recommended [12][13][14]. In this review, we will first (Section 2) review MD simulations of PEGylated biomolecules such as proteins, antimicrobial peptides (AMPs), and coiled coil peptides, focusing on their structural changes induced by PEGylation.…”

“…Figure 1 lists the number of publications on the development of PEG force fields (FFs) and MD simulations of PEGylated biomolecules and nanoparticles. Since all-atom and coarse-grained (CG) PEG FFs have been developed after 1995, short linear PEG chains were mainly simulated up until the 2000s, but recent advances in computer power and simulation methodologies have allowed many more simulations of large complexed (e.g., branched) PEG chains, PEGylated nanoparticle (or protein)-drug complexes and their self-assemblies interacting with plasma proteins and lipid membranes [ 12 , 13 , 14 ]. In particular, simulations have revealed that PEGylation influences the conformations and surface properties of drug molecules or transporters and thus modulates the efficiency of drug delivery and release, which helps explain atomic-level phenomena and determine the optimal size, structure, and density of PEG for drug delivery applications [ 12 , 14 ].…”

“…Note that the conformation of PEGs and their interactions with other molecules can be reasonably predicted only in the presence of accurate FFs. For the development of all-atom [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] and CG models [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ] for PEG and PEO, previous review papers are recommended [ 12 , 13 , 14 ].…”

Mechanistic Understanding From Molecular Dynamics Simulation in Pharmaceutical Research 1: Drug Delivery

“…Li et al carried out a coarse grained MARTINI model simulation to investigate the effect of PEG chain length on the shielding effect of PEGylated nanoparticles (Li and Hu, 2014). A comprehensive review of computational modeling of PEGylation has been written by Souza et al (2018).…”

Effects of site-directed PEGylation on L-asparaginase thermostability

“…Towards the efforts to decrease immunogenicity, studies of derivatives of less immunogenic PEGs such as branched PEGs (Zhang, Liu and Wan, 2014) and hydroxy-PEGs (Saifer et al, 2014;Schellekens, Hennink and Brinks, 2013) are important to explore this unpredictable issue. With the aid of computational techniques, the specific sites at the protein for PEG attachment can be investigated (Sousa et al, 2018). These tests are important to predict the stability and activity of the PEGylated protein.…”