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All Atom Motion Tree detects side chain-related motions and their coupling with domain motion in proteins.

ABSTRACT: Structural changes of proteins are closely related with their molecular function. We previously developed a computational tool, Motion Tree (MT), to compare protein structures and describe structural changes using solely the C? atoms. Here, we have extended MT to incorporate all heavy atoms to analyze side chain-related (SCR) motions. All Atom Motion Tree (AAMT) was applied to 76 proteins that exhibited a simple domain motion identified by MT. AAMT also detected 921 SCR motions. We examined the coupling of domain and SCR motions and classified the structural changes in terms of coupling. The statistical results indicated that it is common for coupled SCR motions to also couple with the domain motion. The classification correlates properties of domain motions and SCR motions. The AAMT results suggest that a large domain motion with a sizable domain boundary is accompanied by SCR motions composed of more than a single residue, which induces further couplings of SCR motions.

SUBMITTER: Koike R

PROVIDER: S-EPMC6976028 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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All Atom Motion Tree detects side chain-related motions and their coupling with domain motion in proteins.

Koike Ryotaro R Ota Motonori M

Biophysics and physicobiology 20191129

Structural changes of proteins are closely related with their molecular function. We previously developed a computational tool, Motion Tree (MT), to compare protein structures and describe structural changes using solely the Cα atoms. Here, we have extended MT to incorporate all heavy atoms to analyze side chain-related (SCR) motions. All Atom Motion Tree (AAMT) was applied to 76 proteins that exhibited a simple domain motion identified by MT. AAMT also detected 921 SCR motions. We examined the ...[more]

PMID: 31984182

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Project description:Many multidomain proteins and ribonucleic acids consist of domains that autonomously fold and that are linked together by flexible junctions. This architectural design allows domains to sample a wide range of positions with respect to one another, yet do so in a way that retains structural specificity, since the number of sampled conformations remains extremely small compared to the total conformations that would be sampled if the domains were connected by an infinitely long linker. This "tuned" flexibility in interdomain conformation is in turn used in many biochemical processes. There is great interest in characterizing the dynamic properties of multidomain systems, and moving beyond conventional descriptions in terms of static structures, toward the characterization of population-weighted ensembles describing a distribution of many conformations sampled in solution. There is also great interest in understanding the design principles and underlying physical and chemical interactions that specify the nature of interdomain flexibility. NMR spectroscopy is one of the most powerful techniques for characterizing motions in complex biomolecules and has contributed greatly toward our basic understanding of dynamics in proteins and nucleic acids and its role in folding, recognition, and signaling. Here, we review methods that have been developed in our laboratories to address these challenges. Our approaches are based on the ability of one domain of the molecule to self-align in a magnetic field, or to dominate the overall orientation of the molecule, so that the conformational freedom of other domains can be assessed by their degree of alignment induced by the aligned part. In turn, this self-alignment ability can be intrinsic or can be caused by tagging appropriate constructs to the molecule of interest. In general, self-alignment is due to magnetic susceptibility anisotropy. Nucleic acids with elongated helices have this feature, as well as several paramagnetic metal centers that can be found in, or attached to, a protein domain.

Project description:The nature of conformational transitions in DNA polymerase lambda (pol lambda), a low-fidelity DNA repair enzyme in the X-family that fills short nucleotide gaps, is investigated. Specifically, to determine whether pol lambda has an induced-fit mechanism and open-to-closed transition before chemistry, we analyze a series of molecular dynamics simulations from both the binary and ternary states before chemistry, with and without the incoming nucleotide, with and without the catalytic Mg(2+) ion in the active site, and with alterations in active site residues Ile(492) and Arg(517). Though flips occurred for several side-chain residues (Ile(492), Tyr(505), Phe(506)) in the active site toward the binary (inactive) conformation and partial DNA motion toward the binary position occurred without the incoming nucleotide, large-scale subdomain motions were not observed in any trajectory from the ternary complex regardless of the presence of the catalytic ion. Simulations from the binary state with incoming nucleotide exhibit more thumb subdomain motion, particularly in the loop containing beta-strand 8 in the thumb, but closing occurred only in the Ile(492)Ala mutant trajectory started from the binary state with incoming nucleotide and both ions. Further connections between active site residues and the DNA position are also revealed through our Ile(492)Ala and Arg(517)Ala mutant studies. Our combined studies suggest that while pol lambda does not demonstrate large-scale subdomain movements as DNA polymerase beta (pol beta), significant DNA motion exists, and there are sequential subtle side chain and other motions-associated with Arg(514), Arg(517), Ile(492), Phe(506), Tyr(505), the DNA, and again Arg(514) and Arg(517)-all coupled to active site divalent ions and the DNA motion. Collectively, these motions transform pol lambda to the chemistry-competent state. Significantly, analogs of these residues in pol beta (Lys(280), Arg(283), Arg(258), Phe(272), and Tyr(271), respectively) have demonstrated roles in determining enzyme efficiency and fidelity. As proposed for pol beta, motions of these residues may serve as gate-keepers by controlling the evolution of the reaction pathway before the chemical reaction.

Dataset Information

All Atom Motion Tree detects side chain-related motions and their coupling with domain motion in proteins.

Publications

All Atom Motion Tree detects side chain-related motions and their coupling with domain motion in proteins.

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