Yuri Hong ^1,2, Saeed Najafi³, Thomas Casey³, Joan-Emma Shea³ ,Song-I Han ^3,4 & Dong Soo Hwang ^1,2

¹School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea. 
²Division of Environmental Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea.
³Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, USA. 
⁴Department of Chemical Engineering, University of California, Santa Barbara, CA 93106, USA.

Corresponding authors : Correspondence to Joan-Emma Shea, Song-I Han or Dong Soo Hwang.

Intrinsically disordered proteins rich in cationic amino acid groups can undergo Liquid-Liquid Phase Separation (LLPS) in the presence of charge-balancing anionic counterparts. Arginine and Lysine are the two most prevalent cationic amino acids in proteins that undergo LLPS, with arginine-rich proteins observed to undergo LLPS more readily than lysine-rich proteins, a feature commonly attributed to arginine's ability to form stronger cation-π interactions with aromatic groups. Here, we show that arginine's ability to promote LLPS is independent of the presence of aromatic partners, and that arginine-rich peptides, but not lysine-rich peptides, display re-entrant phase behavior at high salt concentrations. We further demonstrate that the hydrophobicity of arginine is the determining factor giving rise to the reentrant phase behavior and tunable viscoelastic properties of the dense LLPS phase. Controlling arginine-induced reentrant LLPS behavior using temperature and salt concentration opens avenues for the bioengineering of stress-triggered biological phenomena and drug delivery systems.