Exploring the structure and conformational landscape of human leptin. A molecular dynamics approach.
Leptin is a hormone that regulates energy homeostasis, inflammation, hematopoiesis and immune response, among other functions (Houseknecht et al., 1998; Zhang et al., 1995; Paz-Filho et al., 2010). To obtain its crystallographic structure, it was necessary to substitute a tryptophan for a glutamic acid at position 100, thus creating a mutant leptin that has been reported to have biological activity comparable to the activity of the wild type but that crystallizes more readily. Here, we report a comparative study of the conformational space of WT and W100E leptin using molecular dynamics simulations performed at 300, 400, and 500 K. We detected differences between the interactions of the two proteins with local and distal effects, resulting in changes in the conformation, accessible surface area, compactness, electrostatic potential and dynamic behavior. Additionally, the series of unfolding events that occur when leptin is subjected to high temperature differs for the two constructs. We observed that both proteins are mostly unstructured after 20 ns of MD simulation at 500 K. However, WT leptin maintains a significant amount of secondary structure in helix α2, while the most stable region of W100E leptin is helix α3. Furthermore, we found that the region between residues 25 and 42 might adopt interconverting secondary structures ranging from α-helices and random coils to β-strand structures. Thus, this region can be considered an intrinsically disordered region. This atomistic description supports our understanding of leptin signaling and consequently might facilitate the use of leptin in treatments for the pathophysiologies in which it is implicated.
Laboratorio de Investigación Bioquímica y Biofísica Computacional, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México, D.F. 07320, México.
Brenda
B
Chimal-Vega
Departamento de Fisiología, Doctorado en Ciencias en Biotecnología, ENCB, Instituto Politécnico Nacional. Avenida Wilfrido Massieu s/n, Esq. Manuel L. Stampa, Col. Unidad Profesional Adolfo López Mateos, Delegación Gustavo A. Madero, 07738 México, D.F., México.
Norma
N
Paniagua-Castro
Laboratorio de Investigación Bioquímica y Biofísica Computacional, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México, D.F. 07320, México.
Jonathan
J
Carrillo Vazquez
Laboratorio Transdisciplinario de Investigación en Sistemas Evolutivos, SEPI de la ESCOM del Instituto Politécnico Nacional, Juan de Dios Bátiz y Miguel Othón de Mendizábal s/n, México, D.F. 07738, México.
Jorge L
JL
Rosas-Trigueros
Laboratorio de Investigación Bioquímica y Biofísica Computacional, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México, D.F. 07320, México.
Absalom
A
Zamorano-Carrillo
Laboratorio de Investigación Bioquímica y Biofísica Computacional, Doctorado en Ciencias en Biotecnología, ENMH, Instituto Politécnico Nacional, Guillermo Massieu Helguera, México, D.F. 07320, México. Electronic address: beni1972uk@gmail.com.
Claudia G
CG
Benítez-Cardoza
D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry; D020738:Leptin / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013696:Temperature
D064267:Intrinsically Disordered Proteins; D020738:Leptin
Intrinsically disordered regions; Leptin; Molecular dynamics simulations; Thermal unfolding