TY - JOUR
T1 - Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes
AU - Geng, Chongli
AU - Zeng, Juan
AU - Deng, Xianming
AU - Xia, Fei
AU - Xu, Xin
N1 - Publisher Copyright:
© 2025 American Chemical Society.
PY - 2025/4/3
Y1 - 2025/4/3
N2 - In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)2·CRaf and (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)2·(CRaf)2 might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.
AB - In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that Ras dimerizes in solution and binds stably to Raf, forming Ras·Raf complexes. In this study, we constructed the ternary and quaternary complexes of KRas and CRaf based on crystal structures, denoted as (KRas)2·CRaf and (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed to investigate the stability of these complexes, while hydrogen bonds as well as salt bridges formed at the protein-protein interaction interfaces were analyzed based on simulation trajectories. The results revealed that the KRas·CRaf complex is more stable in explicit solvent compared with the KRas dimer. Formation of the stable quaternary complex (KRas)2·(CRaf)2 might be attributed to the association of two binary KRas·CRaf complexes. Additionally, MD simulations of the KRasG12D·CRaf complex revealed a stable and extended binding site at the KRas-CRaf interaction interface. This binding site was identified as a potential therapeutic target to block abnormal signal transmission in the pathway.
UR - https://www.scopus.com/pages/publications/105001998799
U2 - 10.1021/acs.jpcb.4c08767
DO - 10.1021/acs.jpcb.4c08767
M3 - 文章
C2 - 40126127
AN - SCOPUS:105001998799
SN - 1520-6106
VL - 129
SP - 3306
EP - 3316
JO - Journal of Physical Chemistry B
JF - Journal of Physical Chemistry B
IS - 13
ER -