title: Geometric analysis characterizes molecular rigidity in generic and non-generic protein configurations.
abstract: Proteins operate and interact with partners by dynamically exchanging between functional substates of a conformational ensemble on a rugged free energy landscape. Understanding how these substates are linked by coordinated, collective motions requires exploring a high-dimensional space, which remains a tremendous challenge. While molecular dynamics simulations can provide atomically detailed insight into the dynamics, computational demands to adequately sample conformational ensembles of large biomolecules and their complexes often require tremendous resources. Kinematic models can provide high-level insights into conformational ensembles and molecular rigidity beyond the reach of molecular dynamics by reducing the dimensionality of the search space. Here, we model a protein as a kinematic linkage and present a new geometric method to characterize molecular rigidity from the constraint manifoldQand its tangent spaceQat the current configurationq. In contrast to methods based on combinatorial constraint counting, our method is valid for both generic and non-generic, e.g., singular configurations. Importantly, our geometric approach provides an explicit basis for collective motions along floppy modes, resulting in an efficient procedure to probe conformational space. An atomically detailed structural characterization of coordinated, collective motions would allow us to engineer or allosterically modulate biomolecules by selectively stabilizing conformations that enhance or inhibit function with broad implications for human health.
authors.affiliation: Chair of Applied Dynamics, University of Erlangen-Nuremberg, Haberstrasse 1, 91058 Erlangen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Budday
authors.affiliation: Chair of Applied Dynamics, University of Erlangen-Nuremberg, Haberstrasse 1, 91058 Erlangen, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Leyendecker
authors.affiliation: Division of Biosciences, SLAC National Accelerator Laboratory, Stanford University, 2575 Sand Hill Road, Menlo Park, CA, 94025 USA.
authors.forename: Henry
authors.initials: H
authors.lastname: van den Bedem
keywords: Conformational sampling; Nullspace; Protein; Protein collective motions; Rigidity; Singular configuration