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Physics-based modeling provides predictive understanding of selectively promiscuous substrate binding by Hsp70 chaperones.

ABSTRACT: To help cells cope with protein misfolding and aggregation, Hsp70 molecular chaperones selectively bind a variety of sequences ("selective promiscuity"). Statistical analyses from substrate-derived peptide arrays reveal that DnaK, the E. coli Hsp70, binds to sequences containing three to five branched hydrophobic residues, although otherwise the specific amino acids can vary considerably. Several high-resolution structures of the substrate -binding domain (SBD) of DnaK bound to peptides reveal a highly conserved configuration of the bound substrate and further suggest that the substrate-binding cleft consists of five largely independent sites for interaction with five consecutive substrate residues. Importantly, both substrate backbone orientations (N- to C- and C- to N-) allow essentially the same backbone hydrogen-bonding and side-chain interactions with the chaperone. In order to rationalize these observations, we performed atomistic molecular dynamics simulations to sample the interactions of all 20 amino acid side chains in each of the five sites of the chaperone in the context of the conserved substrate backbone configurations. The resulting interaction energetics provide the basis set for deriving a predictive model that we call Paladin (Physics-based model of DnaK-Substrate Binding). Trained using available peptide array data, Paladin can distinguish binders and nonbinders of DnaK with accuracy comparable to existing predictors and further predicts the detailed configuration of the bound sequence. Tested using existing DnaK-peptide structures, Paladin correctly predicted the binding register in 10 out of 13 substrate sequences that bind in the N- to C- orientation, and the binding orientation in 16 out of 22 sequences. The physical basis of the Paladin model provides insight into the origins of how Hsp70s bind substrates with a balance of selectivity and promiscuity. The approach described here can be extended to other Hsp70s where extensive peptide array data is not available.

SUBMITTER: Nordquist EB

PROVIDER: S-EPMC8604352 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Modeling Instruction (MI) for University Physics is a curricular and pedagogical approach to active learning in introductory physics. A basic tenet of science is that it is a model-driven endeavor that involves building models, then validating, deploying, and ultimately revising them in an iterative fashion. MI was developed to provide students a facsimile in the university classroom of this foundational scientific practice. As a curriculum, MI employs conceptual scientific models as the basis for the course content, and thus learning in a MI classroom involves students appropriating scientific models for their own use. Over the last 10 years, substantial evidence has accumulated supporting MI's efficacy, including gains in conceptual understanding, odds of success, attitudes toward learning, self-efficacy, and social networks centered around physics learning. However, we still do not fully understand the mechanisms of how students learn physics and develop mental models of physical phenomena. Herein, we explore the hypothesis that the MI curriculum and pedagogy promotes student engagement via conceptual model building. This emphasis on conceptual model building, in turn, leads to improved knowledge organization and problem solving abilities that manifest as quantifiable functional brain changes that can be assessed with functional magnetic resonance imaging (fMRI). We conducted a neuroeducation study wherein students completed a physics reasoning task while undergoing fMRI scanning before (pre) and after (post) completing a MI introductory physics course. Preliminary results indicated that performance of the physics reasoning task was linked with increased brain activity notably in lateral prefrontal and parietal cortices that previously have been associated with attention, working memory, and problem solving, and are collectively referred to as the central executive network. Critically, assessment of changes in brain activity during the physics reasoning task from pre- vs. post-instruction identified increased activity after the course notably in the posterior cingulate cortex (a brain region previously linked with episodic memory and self-referential thought) and in the frontal poles (regions linked with learning). These preliminary outcomes highlight brain regions linked with physics reasoning and, critically, suggest that brain activity during physics reasoning is modifiable by thoughtfully designed curriculum and pedagogy.

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Physics-based modeling provides predictive understanding of selectively promiscuous substrate binding by Hsp70 chaperones.

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