TY - JOUR
T1 - Exploring the structure and conformational landscape of human leptin. A molecular dynamics approach
AU - Chimal-Vega, Brenda
AU - Paniagua-Castro, Norma
AU - Carrillo Vazquez, Jonathan
AU - Rosas-Trigueros, Jorge L.
AU - Zamorano-Carrillo, Absalom
AU - Benítez-Cardoza, Claudia G.
N1 - Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/11/21
Y1 - 2015/11/21
N2 - 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.
AB - 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.
KW - Intrinsically disordered regions
KW - Leptin
KW - Molecular dynamics simulations
KW - Thermal unfolding
UR - http://www.scopus.com/inward/record.url?scp=84941948650&partnerID=8YFLogxK
U2 - 10.1016/j.jtbi.2015.08.014
DO - 10.1016/j.jtbi.2015.08.014
M3 - Artículo
C2 - 26342543
SN - 0022-5193
VL - 385
SP - 90
EP - 101
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
ER -