95
Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I
42-POS
Board 42
Multiple Pre-Existence of Conformations Underpinning Allosteric Activation of Gal3p in
Galactose Signal Transduction
Kharerin Hungyo
, Rajesh K. Kar, Ranjith Padinhateeri, Paike J. Bhat.
Indian institute of Technology Bombay, Mumbai, India.
Conformational dynamics of protein has been considered as one of the key driving forces
regulating cellular signaling. Signaling proteins have been shown to pre-exist predominantly in
inactive conformation (I) untill a ligand or mutation induces a population shift in favor of the
formerly less populated active conformation (A). However, the transition(s) between inactive
and active conformational states has not been clearly elucidated. Here we investigate the
dynamic stability and the role of amino acids involved in stabilization and intra-domain signal
communications in Gal3p, a signal transducer protein in
GAL
genetic switch of
Saccharomyces
cerevisiae
. Gal3p is known to exist in multiple conformational states (I and A). In response to
galactose, Gal3p switches from open conformation (I) to closed conformation (A), to activate
transcription of
GAL
genes. Closed and open conformer dynamics using canonical molecular
dynamics (CMD) simulations were carried out for the wild type protein and its mutant variants.
Distribution of the domain-lip distance from closed and open conformer dynamics shows a
bimodal behavior for the former, while demonstrating a gaussian unimodal for the latter. Using
hydrogen bond (H-bond) network analysis from CMD, we identified set(s) of conserved H-
bonded amino acid pairs that are spaced far apart in the primary structure of the protein(s). Our
results suggest the presence of a typical signature of H-bonded network specific to the state of
the protein (open or closed) as well as varying H-bonded network for different mutant variants
which could play a crucial role in determining their dynamic stability. We also used targeted
molecular dynamics (TMD) simulations to study the free energy landscape along the transitional
pathways from state 'I' to state 'A' in order to identify the transitional structures (local minima)
encountered during the structural switching.
