TY - JOUR
T1 - The molecular basis of IGF-II/IGF2R recognition
T2 - A combined molecular dynamics simulation, free-energy calculation and computational alanine scanning study
AU - Guo, Jingjing
AU - Wang, Xiaoting
AU - Sun, Huijun
AU - Liu, Huanxiang
AU - Yao, Xiaojun
N1 - Funding Information:
This work was supported by the Program for New Century Excellent Talents in University (grant no. NCET-07-0399) and the National Natural Science Foundation of China (grant no. 20905033). The authors also wish to express their thanks to Zhide Foundation of Lanzhou University for supporting this work.
PY - 2012/4
Y1 - 2012/4
N2 - Insulin-like growth factor-II (IGF-II) is a key regulator of cell growth, survival, migration and differentiation, and is thus pivotal in many cancers. An individual with a high IGF-II level is at high risk of developing cancer, whereas IGF2R is implicated as being important in tumor suppression. Thus, uncovering the essence of the IGF-II/ IGF2R interaction is very important to understanding the origin of the tumor-suppressing effect of IGF2R. In this study, in order to investigate the interaction of the IGF-II/ IGF2R complex and to characterize the binding hot spots of this interaction, a 10 ns molecular dynamics simulation combined with MM-PBSA/MM-GBSA computations and computational alanine scanning was performed on the IGFII/ IGF2R complex. From the results of the free-energy decomposition and the computational alanine scanning calculation, we identified the key residues in the IGF-II/ IGF-2R interaction. The results from the calculation were consistent with reported experimental mutagenesis studies. The information on the interaction of IGF-II and IGF2R obtained is vital for understanding how the structure of IGF2R influences the function of IGF-II in growth and development. This study will also lead to new opportunities to develop molecular probes that can assist in diagnostic screening, and even novel approaches to controlling tumor development.
AB - Insulin-like growth factor-II (IGF-II) is a key regulator of cell growth, survival, migration and differentiation, and is thus pivotal in many cancers. An individual with a high IGF-II level is at high risk of developing cancer, whereas IGF2R is implicated as being important in tumor suppression. Thus, uncovering the essence of the IGF-II/ IGF2R interaction is very important to understanding the origin of the tumor-suppressing effect of IGF2R. In this study, in order to investigate the interaction of the IGF-II/ IGF2R complex and to characterize the binding hot spots of this interaction, a 10 ns molecular dynamics simulation combined with MM-PBSA/MM-GBSA computations and computational alanine scanning was performed on the IGFII/ IGF2R complex. From the results of the free-energy decomposition and the computational alanine scanning calculation, we identified the key residues in the IGF-II/ IGF-2R interaction. The results from the calculation were consistent with reported experimental mutagenesis studies. The information on the interaction of IGF-II and IGF2R obtained is vital for understanding how the structure of IGF2R influences the function of IGF-II in growth and development. This study will also lead to new opportunities to develop molecular probes that can assist in diagnostic screening, and even novel approaches to controlling tumor development.
KW - Computational alanine scanning
KW - IGF-II/IGF2R interaction
KW - Molecular dynamics simulation
KW - Molecular mechanics generalized born surface area (MM-GBSA)
KW - Protein-protein interaction
UR - http://www.scopus.com/inward/record.url?scp=84861229091&partnerID=8YFLogxK
U2 - 10.1007/s00894-011-1159-4
DO - 10.1007/s00894-011-1159-4
M3 - Article
C2 - 21761181
AN - SCOPUS:84861229091
SN - 1610-2940
VL - 18
SP - 1421
EP - 1430
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
IS - 4
ER -
