Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Incorporating currently (June 21, 2021) available experimental structural data in PDB of semaglutide and GLP-1R, and with a set of computational structural and biophysical analysis, this short paper for the first time puts forward an experimentally testable hypothesis: semaglutide is able to bind tighter to GLP-1R via a simple Val27-Arg28 exchange in its peptide backbone.

Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by the Glu6Val mutation in the β chain (Hb) of the oxygen-carrying hemoglobin protein in sicklemia patients. In the molecular pathogenesis of SCD, the sickle hemoglobin (Hb-S) polymerization is a major driver for structural deformation of red blood cells, i.e. red blood cell (RBC) sickling. Biophysically, it still remains elusive how this SCD-linked E6V mutation leads to Hb-S polymerization in RBC sickling. Therefore, with a comprehensive set of analysis of experimental Hb structures, this letter highlights electrostatic repulsion as a key biophysical mechanism of Hb-S polymerization in RBC sickling, which provides atomic-level insights into the functional impact of the SCD-linked E6V substitution from a biophysical point of view. SIGNIFICANCE During the past 25 years, a total of 104 Hb-related structures have been deposited in PDB. For the first time, this article presents a comprehensive set of electrostatic analysis of the 104 experimental structures, highlighting electrostatic repulsion as a fundamental biophysical mechanism for Hb-S polymerization in RBC sickling. The structural and electrostatic analysis here also provides biophysical insights into the functional impact of the SCD-linked E6V substitution.