Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

6-POS Board 6 Hierarchical, Structural Basis for Motions Encoding HDXMS Data Dominik Budday 1 , Sigrid Leyendecker 1 , Henry Van den Bedem 2 . 1 University of Erlangen-Nuremberg, Erlangen, Germany, 2 Stanford University, Menlo Park, CA, USA. Hydrogen-Deuterium Exchange Mass Spectroscopy (HDXMS) can provide important experimental insights into functional dynamics based on neutron exchange between protein and solvent. Differences in Deuterium exchange by the protein between wild-type and mutants, or across different members of a protein family can relate structural dynamics with function. However, the long time-scales of HDXMS experiments often make data interpretation challenging. The availability of computational methods capable of resolving these spatio- temporal scales could result in broader adoption of HDXMS. Here, we adapt Kino-Geometric Sampling (KGS) to provide a structural basis for motions with hierarchically increasing hydrogen bond violations. Our geometric approach encodes hydrogen bonds as holonomic constraints, imposing collective motions on the dihedral degrees of freedom to maintain cycle-closure. A singular value decomposition of the constraint Jacobian ranks independent, orthonormal motion modes by constraint violation, reminiscent of normal modes that describe functionally relevant motions at low eigenfrequencies. The method is based on the hypothesis that violations of the hydrogen bond network geometrically encoded in KGS is related to functional, dynamic exchange in the molecule. Our kinematic, time-independent analysis is very fast and applicable to proteins and RNA, making it suitable to study motions across spatio-temporal scales in a matter of seconds. Predictions from KGS hierarchical motions on exchanging hydrogen bonds show qualitative agreement with HDXMS measurements in the α-subunit of protein Gs. We further compare our predictions with the Start2Fold database which provides a collection of sparse data on folding cooperativity and stability of proteins measured by HDXMS and related experimental methods. Initial results are promising and strengthen our hypothesis, displaying a fast, yet detailed computational tool to interpret and predict hydrogen-deuterium exchange in macromolecules.

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