Biophysical Society Thematic Meeting | Trieste 2024

Emerging Theoretical Approaches to Complement Single-Particle Cryo-EM

Tuesday Speaker Abstracts

INTEGRATIVE MODELING OF PROTEIN STRUCTURE AND DYNAMICS USING MD SIMULATIONS AND EXPERIMENTAL DATA Yuji Sugita 1,2,3 ; Mao Oide 1,4 ; Teppei Ikeya 5 ; Yutaka Ito 5 ; 1 RIKEN, Cluster for Pioneering Research, Wako, Japan 2 RIKEN, Center for Computational Science, Kobe, Japan 3 RIKEN, Center for Biosystems Dynamics Research, Kobe, Japan 4 Osaka University, Institute for Protein Research, Suita, Japan 5 Tokyo Metoropolitan University, Department of Chemistry, Hachioji, Japan Multi-domain proteins often have flexible conformations in the solution or the cell. Although X ray crystal structures of these proteins are available, inconsistency between the crystal structures and other experimental measurements has often been observed. We aim to solve such a problem by developing an integrative modeling approach based on MD simulations and several experimental data. In our integrative modeling approach, we rely on MELD (Modeling Employing Limited Data), a Bayesian method, to selectively use only reliable experimental data. We apply this method to the solution structure ensembles of Growth factor receptor bound protein 2 (GRB2), which is one of the critical proteins to recognize the tyrosine phosphorylation of the epidermal growth factor receptor (EGFR). Our integrative modeling method successfully resolved the inconsistency between X-ray crystal structures, solution nuclear magnetic resonance (NMR), and small-angle X-ray scattering (SAXS) experiments. It also provides representative structures with their statistical weights.

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