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\begin{document}

\title{Synergy and Anti-Cooperativity in Allostery: Molecular Dynamics Study of
WT and Oncogenic KRAS-RGL1}



\author[1]{Burak Erman}%
\author[2]{Aysima Hacisuleyman}%
\affil[1]{Vehbi Koc Vakfi}%
\affil[2]{Universite de Lausanne Departement de biologie computationnelle}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\begin{abstract}
This study focuses on investigating the effects of an oncogenic mutation
(G12V) on the stability and interactions within the KRAS-RGL1 protein
complex. The KRAS-RGL1 complex is of particular interest due to its
relevance to KRAS-associated cancers and the potential for developing
targeted drugs against the KRAS system. The stability of the complex and
the allosteric effects of specific residues are examined to understand
their roles as modulators of complex stability and function. Using
molecular dynamics simulations, we calculate the mutual information, MI,
between two neighboring residues at the interface of the KRAS-RGL1
complex, and employ the concept of interaction information, II, to
measure the contribution of a third residue to the interaction between
interface residue pairs. Negative II indicates synergy, where the
presence of the third residue strengthens the interaction, while
positive II suggests anti-cooperativity. Our findings reveal that MI
serves as a dominant factor in determining the results, with the G12V
mutation increasing the MI between interface residues, indicating
enhanced correlations due to the formation of a more compact structure
in the complex. Interestingly, although II plays a role in understanding
three-body interactions and the impact of distant residues, it is not
significant enough to outweigh the influence of MI in determining the
overall stability of the complex. Nevertheless, II may nonetheless be a
relevant factor to consider in future drug design efforts. This study
provides valuable insights into the mechanisms of complex stability and
function, highlighting the significance of three-body interactions and
the impact of distant residues on the binding stability of the complex.
Additionally, our findings demonstrate that constraining the
fluctuations of a third residue consistently increases the stability of
the G12V variant, making it challenging to weaken complex formation of
the mutated species through allosteric manipulation. The novel
perspective offered by this approach on protein dynamics, function, and
allostery has potential implications for understanding and targeting
other protein complexes involved in vital cellular processes. The
results contribute to our understanding of the effects of oncogenic
mutations on protein-protein interactions and provide a foundation for
future therapeutic interventions in the context of KRAS-associated
cancers and beyond.%
\end{abstract}%



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