Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes DOI

Chao Geng,

Juan Zeng, Xianming Deng

et al.

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that dimerizes in solution binds stably Raf, forming Ras·Raf complexes. this study, we constructed ternary quaternary complexes of KRas CRaf based on crystal structures, denoted as (KRas)2·CRaf (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed investigate stability these complexes, while hydrogen bonds well salt bridges formed at protein–protein interaction interfaces analyzed simulation trajectories. The results revealed KRas·CRaf complex is more stable explicit solvent compared with dimer. Formation (KRas)2·(CRaf)2 might be attributed association two binary Additionally, MD KRasG12D·CRaf extended binding site KRas–CRaf interface. This was identified potential therapeutic target block abnormal signal transmission pathway.

Language: Английский

Deciphering allosteric mechanisms in KRAS activation: insights from GTP-induced conformational dynamics and interaction network reorganization DOI Creative Commons

Dongmei Zhao,

Jingyu Yang,

Meng-Ting Liu

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(3), P. 2261 - 2274

Published: Jan. 1, 2025

KRAS activation is driven by GTP binding, leading to increased flexibility and dynamic network reorganization. This study highlights the critical roles of switch I, II, P-loop in mediating allosteric signaling pathways.

Language: Английский

Citations

1
A review on description dynamics and conformational changes of proteins using combination of principal component analysis and molecular dynamics simulation DOI
Sajad Moradi, Amin Nowroozi,

Mohammad Aryaei Nezhad

et al.

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 183, P. 109245 - 109245

Published: Oct. 9, 2024

Language: Английский

Citations

5
Accurate Characterization of the Allosteric Energy Landscapes, Binding Hotspots and Long-Range Communications for KRAS Complexes with Effector Proteins : Integrative Approach Using Microsecond Molecular Dynamics, Deep Mutational Scanning of Binding Energetics and Allosteric Network Modeling DOI Open Access
Sian Xiao, Mohammed Merae Alshahrani,

Guang Hu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

KRAS is a pivotal oncoprotein that regulates cell proliferation and survival through interactions with downstream effectors such as RAF1. Oncogenic mutations in KRAS, including G12V, G13D, Q61R, drive constitutive activation hyperactivation of signaling pathways, contributing to cancer progression. Despite significant advances understanding biology, the structural dynamic mechanisms binding allostery by which oncogenic enhance KRAS-RAF1 remain incompletely understood. In this study, we employ microsecond molecular dynamics simulations, Markov State Modeling, mutational scanning free energy calculations together network modeling elucidate effect characterize thermodynamic allosteric drivers hotspots activation. Our simulations revealed stabilize open active conformation differentially modulating flexibility switch I II regions, thereby enhancing RAF1 affinity. The G12V mutation rigidifies both II, locking stable, state. contrast, G13D moderately reduces while increasing dynamics, restoring balance between stability flexibility. Q61R induces more complex conformational landscape, characterized increased expansion functional macrostates, promotes prolonged signaling. Mutational complexes identified key affinity hotspots, Y40, E37, D38, D33, MM-GBSA analysis leverage synergistic electrostatic hydrophobic stabilizing complexes. Network-based communication identifies critical residues (e.g., L6, D57, R97) mediate long-range core interface. central β-sheet emerges hub for transmitting changes, linking distant sites facilitating regulation. Strikingly, predicted align experimentally define landscape allostery. This study highlights power integrating computational experimental data unravel its mutants. identification routes offers new opportunities developing targeted therapies disrupt inhibit results underscore potential approaches guide design inhibitors mutant-specific KRAS-driven cancers.

Language: Английский

Citations

0
Large-Scale AI-Based Structure and Activity Prediction Analysis of ShK Domain Peptides from Sea Anemones in the South China Sea DOI Creative Commons
Hua Zheng, Li‐Min Lin,

Wanting Yang

et al.

Marine Drugs, Journal Year: 2025, Volume and Issue: 23(2), P. 85 - 85

Published: Feb. 16, 2025

Sea anemone peptides represent a valuable class of biomolecules in the marine toxin library due to their various structures and functions. Among these, ShK domain are particularly notable for selective inhibition Kv1.3 channel, holding great potential applications immune regulation treatment metabolic disorders. However, these peptides' structural complexity diversity have posed challenges functional prediction. In this study, we compared 36 from four species sea South China explored binding ability with channels by combining molecular docking dynamics simulation studies. Our findings highlight that variations loop length, residue composition, charge distribution among affect stability specificity. This work presents an efficient strategy large-scale peptide structure prediction activity screening, providing foundation future pharmacological research.

Language: Английский

Citations

0
Dynamic Coupling and Entropy Changes in KRAS G12D Mutation: Insights into Molecular Flexibility, Allostery and Function DOI
Aysima Hacisuleyman, Deniz Yüret, Burak Erman

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169075 - 169075

Published: March 1, 2025

Language: Английский

Citations

0
Atomistic Profiling of KRAS Interactions with Monobodies and Affimer Proteins Through Ensemble-Based Mutational Scanning Unveils Conserved Residue Networks Linking Cryptic Pockets and Regulating Mechanisms of Binding, Specificity and Allostery DOI
Mohammed Alshahrani,

Vedant Parikh,

Brian Foley

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 14, 2025

KRAS, a historically "undruggable" oncogenic driver, has eluded targeted therapies due to its lack of accessible binding pockets in active state. This study investigates the conformational dynamics, mechanisms, and allosteric communication networks KRAS complexes with monobodies (12D1, 12D5) affimer proteins (K6, K3, K69) characterize mechanisms hotspots binding. Through molecular dynamics simulations, mutational scanning, free energy analysis network-based analyses, we identified conserved that serve as critical nodes for long-range KRAS. Key residues β-strand 4 (F78, L80, F82), α-helix 3 (I93, H95, Y96), 5 (V114, N116), (Y157, L159, R164) consistently emerged across diverse partners, forming contiguous linking functional regions Notably, acts central hub propagating changes, while cryptic pocket centered around H95/Y96 positions by clinically approved inhibitors was universal hotspot both allostery. The also reveals interplay between structural rigidity flexibility, where stabilization one region induces compensatory flexibility others, reflecting KRAS's adaptability perturbations. We found stabilize switch II disrupting coupling I leading enhanced mobility Similarly, K3 leverages α3-helix hinge point amplify effects on dynamics. Mutational scanning highlighted energetic drivers interactions. revealing key residues, including H95 Y96 α3 helix, major contributors affinity selectivity. Network distant sites. predicted strongly aligned experimental data, validating robustness computational approach. Despite distinct interfaces, shared highlight infrastructure, reinforcing their importance signaling. results this can inform rational design small-molecule mimic proteins, challenging reputation

Language: Английский

Citations

0
Molecular Dynamics Investigation into the Stability of KRas and CRaf Multimeric Complexes DOI

Chao Geng,

Juan Zeng, Xianming Deng

et al.

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: March 24, 2025

In the Ras/Raf/MAPK signaling pathway, Ras and Raf proteins interact synergistically to form a tetrameric complex. NMR experiments have demonstrated that dimerizes in solution binds stably Raf, forming Ras·Raf complexes. this study, we constructed ternary quaternary complexes of KRas CRaf based on crystal structures, denoted as (KRas)2·CRaf (KRas)2·(CRaf)2, respectively. Molecular dynamics (MD) simulations were performed investigate stability these complexes, while hydrogen bonds well salt bridges formed at protein–protein interaction interfaces analyzed simulation trajectories. The results revealed KRas·CRaf complex is more stable explicit solvent compared with dimer. Formation (KRas)2·(CRaf)2 might be attributed association two binary Additionally, MD KRasG12D·CRaf extended binding site KRas–CRaf interface. This was identified potential therapeutic target block abnormal signal transmission pathway.

Language: Английский

Citations

0