Computational Study of Complex Formation between Hyaluronan Polymers and Polyarginine Peptides at Various Ratios

Hyaluronic acid, a naturally occurring carbohydrate biopolymer in human tissues, finds wide application in cosmetics, medicine, and material science. Its anionic properties play a crucial role in its interaction with positively charged macromolecules and ions. Among these macromolecules, positively charged arginine molecules or polyarginine peptides demonstrate potential in drug delivery when complexed with hyaluronan. This study aimed to compare and elucidate the results of both experimental and computational investigations on the interactions between hyaluronic acid polymers and polyarginine peptides. Experimental findings revealed that by varying the length of polyarginine peptides and the molar ratio, it is possible to modulate the size, solubility, and stability of hyaluronan–arginine particles. To further explore these interactions, molecular dynamics simulations were conducted to model the complexes formed between hyaluronic acid polymers and arginine peptides. The simulations are considered in different molar ratios and lengths of polyarginine peptides. By analysis of the data, we successfully determined the shape and size of the resulting complexes. Additionally, we identified the primary driving forces behind complex formation and explained the observed variations in peptide interactions with hyaluronan.


Table of Contents
) with respect to the extended conformation of HA .

Fig. S3. Shapes of particles of the systems with Arg10
A-E. Shapes are shown for the snapshots as formed at the end of the MD.The color scheme and representation is similar to Fig. S2.Inset in Fig. S2.E shows complex networks formed in the case of the PBC problem.

Fig. S1 .
Fig. S1.Shapes of particles formed in small systems

Fig. S2 .
Fig. S2.Shapes of particles A-F.Shapes are shown for the snapshots as formed at the end of the MD.One HA polymer is colored red, the other blue; polyarginine peptides are represented by molecular surface and colored according to the atom name.The upper figure in each panel represents an HA-polyarginine peptide complex (except for Fig. S2.A), the lower only HA.The RMSD and RMSF graphs of HA molecules are shown under each representation.RMSF are calculated for the stable period of MD (listed in the TableS1) with respect to the extended conformation of HA .
HA.There are 2 molecules of HA in each simulation, denoted as HA-1 and HA-2, each is formed by 25 HA units.The RMSF of HA molecules simulated without polyarginine peptides are also shown for comparison (red lines).Data are split into 2 sets: A. Systems with different lengths of polyarginine peptide; B. Systems with different molar ratios 1 (N) and a similar length of polyarginine peptide (all are for MD with Arg10).

Table S2 . Summary of HBs formed during MD Maximum
values in columns for 2HA25 polymer are highlighted in bold and italics, minimum in underlined italics.Number of hydrogen bonds is calculated for equilibrated period of MD.
* Normalization is performed to the number of Arg residues.** Total number of HBs formed by the system HA-Arg is the sum of HBs for Arg-water and HBs for HA-water.