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Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides.

ABSTRACT: The intrinsic conformational preferences of small peptides may provide additional insight into the thermodynamics and kinetics of protein folding. In this study, we explore the underlying energy landscapes of two model peptides, namely, Ac-Ala-NH₂ and Ac-Ser-NH₂, using geometry-optimization-based tools developed within the context of energy landscape theory. We analyze not only how side-chain polarity influences the structural preferences of the dipeptides, but also other emergent properties of the landscape, including heat capacity profiles, and kinetics of conformational rearrangements. The contrasting topographies of the free energy landscape agree with recent results from Fourier transform microwave spectroscopy experiments, where Ac-Ala-NH₂ was found to exist as a mixture of two conformers, while Ac-Ser-NH₂ remained structurally locked, despite exhibiting an apparently rich conformational landscape.

SUBMITTER: Chakraborty D

PROVIDER: S-EPMC8279551 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides.

Chakraborty Debayan D Banerjee Atreyee A Wales David J DJ

The journal of physical chemistry. B 20210526 22

The intrinsic conformational preferences of small peptides may provide additional insight into the thermodynamics and kinetics of protein folding. In this study, we explore the underlying energy landscapes of two model peptides, namely, Ac-Ala-NH<sub>2</sub> and Ac-Ser-NH<sub>2</sub>, using geometry-optimization-based tools developed within the context of energy landscape theory. We analyze not only how side-chain polarity influences the structural preferences of the dipeptides, but also other e ...[more]

PMID: 34037392

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Project description:The three-dimensional structures of the dihydrofolate reductase enzymes from Escherichia coli (ecDHFR or ecE) and Homo sapiens (hDHFR or hE) are very similar, despite a rather low level of sequence identity. Whereas the active site loops of ecDHFR undergo major conformational rearrangements during progression through the reaction cycle, hDHFR remains fixed in a closed loop conformation in all of its catalytic intermediates. To elucidate the structural and dynamic differences between the human and E. coli enzymes, we conducted a comprehensive analysis of side chain flexibility and dynamics in complexes of hDHFR that represent intermediates in the major catalytic cycle. Nuclear magnetic resonance relaxation dispersion experiments show that, in marked contrast to the functionally important motions that feature prominently in the catalytic intermediates of ecDHFR, millisecond time scale fluctuations cannot be detected for hDHFR side chains. Ligand flux in hDHFR is thought to be mediated by conformational changes between a hinge-open state when the substrate/product-binding pocket is vacant and a hinge-closed state when this pocket is occupied. Comparison of X-ray structures of hinge-open and hinge-closed states shows that helix αF changes position by sliding between the two states. Analysis of χ1 rotamer populations derived from measurements of (3)JCγCO and (3)JCγN couplings indicates that many of the side chains that contact helix αF exhibit rotamer averaging that may facilitate the conformational change. The χ1 rotamer adopted by the Phe31 side chain depends upon whether the active site contains the substrate or product. In the holoenzyme (the binary complex of hDHFR with reduced nicotinamide adenine dinucleotide phosphate), a combination of hinge opening and a change in the Phe31 χ1 rotamer opens the active site to facilitate entry of the substrate. Overall, the data suggest that, unlike ecDHFR, hDHFR requires minimal backbone conformational rearrangement as it proceeds through its enzymatic cycle, but that ligand flux is brokered by more subtle conformational changes that depend on the side chain motions of critical residues.

Dataset Information

Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides.

Publications

Side-Chain Polarity Modulates the Intrinsic Conformational Landscape of Model Dipeptides.

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