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1.
J Chem Phys ; 152(3): 035103, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31968956

RESUMO

The molecular dynamics (MD) computer simulation technique is powerful for the investigation of conformational equilibrium properties of biomolecules. In particular, free energy surfaces of the torsion angles (those degrees of freedom from which the geometry mostly depends) allow one to access conformational states, as well as kinetic information, i.e., if the transitions between conformational states occur by simple jumps between wells or if conformational regions close to these states also are populated. The information obtained from MD simulations may depend substantially on the force field employed, and thus, a validation procedure is essential. NMR relaxation data are expected to be highly sensitive to the details of the torsional free energy surface. As a case-study, we consider the disaccharide α-l-Rhap-(1 → 2)-α-l-Rhap-OMe that features only two important torsion angles, ϕ and ψ, which define the interglycosidic orientation of the sugar residues relative to each other, governed mainly by the exo-anomeric effect and steric interactions, respectively. In water, a ψ- state is preferred, whereas in DMSO, it is a ψ+ state, suggesting inherent flexibility at the torsion angle. MD simulations indicated that bistable potentials describe the conformational region well. To test whether a unimodal distribution suffices or if a bimodal distribution better represents molecular conformational preferences, we performed an alchemical morphing of the torsional free energy surface and computed T1, T2, and NOE13C NMR relaxation data that were compared to experimental data. All three NMR observables are substantially affected by the morphing procedure, and the results strongly support a bimodal Boltzmann equilibrium density with a major and a minor conformational state bisected at ψ ≈ 0°, in accord with MD simulations in an explicit solvent.

2.
Phys Chem Chem Phys ; 22(6): 3455-3465, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31984980

RESUMO

We propose an approach to the evaluation of kinetic rates of elementary chemical reactions within Kramers' theory based on the definition of the reaction coordinate as a linear combination of natural, pseudo Z-matrix, internal coordinates of the system. The element of novelty is the possibility to evaluate the friction along the reaction coordinate, within a hydrodynamic framework developed recently [J. Campeggio et al., J. Comput. Chem. 2019, 40, 679-705]. This, in turn, allows to keep into account barrier recrossing, i.e. the transmission coefficient that is employed in correcting transition state theory evaluations. To test the capabilities and the flaws of the approach we use as case studies two archetypal SN2 reactions. First, we consider to the standard substitution of chloride ion to bromomethane. The rate constant at 295.15 K is evaluated to k/c⊖ = 2.7 × 10-6 s-1 (with c⊖ = 1 M), which compares well to the experimental value of 3.3 × 10-6 s-1 [R. H. Bathgate and E. A. Melwyn-Hughes, J. Chem. Soc 1959, 2642-2648]. Then, the method is applied to the SN2 reaction of methylthiolate to dimethyl disulfide in water. In biology, such an interconversion of thiols and disulfides is an important metabolic topic still not entirely rationalized. The predicted rate constant is k/c⊖ = 7.7 × 103 s-1. No experimental data is available for such a reaction, but it is in accord with the fact that the alkyl thiolates to dialkyl disulfides substitutions in water have been found to be fast reactions [S. M. Bachrach, J. M. Hayes, T. Dao and J. L. Mynar, Theor. Chem. Acc. 2002, 107, 266-271].

3.
J Phys Chem B ; 123(38): 8019-8033, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31469564

RESUMO

We have developed a new molecular dynamics (MD) based method for describing analytically local potentials at mobile N-H sites in proteins. Here we apply it to the monomer and dimer of the Rho GTPase binding domain (RBD) of the transmembrane receptor plexin-B1 to gain insight into dimerization, which can compete with Rho GTPase binding. In our method, the local potential is given by linear combinations, u(DL,K), of the real combinations of the Wigner rotation matrix elements, DL,K, with L = 1-4 and appropriate symmetry. The combination that "fits best" the corresponding MD potential of mean force, u(MD), is the potential we are seeking, u(DL,K - BEST). For practical reasons the fitting process involves probability distributions, Peq ∝ exp(-u), instead of potentials, u. The symmetry of the potential, u(DL,K), may be related to the irreducible representations of the D2h point group. The monomer (dimer) potentials have mostly Ag and B2u (B1u and B2u) symmetry. For the monomer, the associated probability distributions are generally dispersed in space, shallow, and centered at the "reference N-H orientation" (defined in section 3.1. below); for the dimer many are more concentrated, deep and centered away from the "reference N-H orientation". The u(DL,K) functions provide a consistent description of the potential energy landscape at protein N-H sites. The L1-loop of the plexin-B1 RBD is not seen in the crystal structure, and many resonances of the L4 loop are missing in the NMR 15N-1H HSQC spectrum of the dimer; we suggest reasons for these features. An allosteric signal transmission pathway was reported previously for the monomer. We find that it has shallow N-H potentials at its ends, which become deeper as one proceeds toward the middle, complementing structurally the previously derived dynamic picture. Prospects of this study include correlating u(DL,K - BEST) with MD force-fields, and using them without further adjustment in NMR relaxation analysis schemes.

4.
ChemSusChem ; 12(18): 4229-4239, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31309717

RESUMO

The metal-support interactions between sulfur-doped carbon supports (SMCs) and Pt nanoparticles (NPs) were investigated, aiming at verifying how sulfur functional groups can improve the electrocatalytic performance of Pt NPs towards the oxygen reduction reaction (ORR). SMCs were synthetized, tailoring the density of sulfur functional groups, and Pt NPs were deposited by thermal reduction of Pt(acac)2 . The extent of the metal-support interaction was proved by X-ray photoelectron spectroscopy (XPS) analysis, which revealed a strong electronic interaction, proportional to the density of sulfur defects, whereas XRD spectra provided evidence of higher strain in Pt NPs loaded on SMC. DFT simulations confirmed that the metal-support interaction was strongest in the presence of a high density of sulfur defects. The combination of microstrain and electronic effects resulted in a high catalytic activity of supported Pt NPs towards ORR, with linear correlations of the half-wave potential E1/2 or the kinetic current jk with the sulfur content in the support. Furthermore, a mass activity value (550 A g-1 ) well above the United States Department of Energy target of 440 A g-1 at 0.9 V (vs. reversible hydrogen electrode, RHE), was determined.

5.
J Chem Phys ; 150(18): 184108, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091922

RESUMO

In Paper I [Polimeno et al., J. Chem. Phys. 150, 184107 (2019)], we proposed a general approach for interpreting relaxation properties of a macromolecule in solution, derived from an atomistic description. A simple scheme (the semiflexible Brownian, SFB, model) has been defined for the case of limited internal flexibility, but retaining full coupling with external degrees of freedom, inclusion of all of the momenta, and dissipation. Here we discuss the application of the SFB model to the practical evaluation of orientation spectral densities, based on two complementary computational treatments.

6.
J Chem Phys ; 150(18): 184107, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091939

RESUMO

A framework for the stochastic description of relaxation processes in flexible macromolecules, including dissipative effects, is introduced from an atomistic point of view. Projection-operator techniques are employed to obtain multidimensional Fokker-Planck operators governing the relaxation of internal coordinates and global degrees of freedom and depending upon parameters fully recoverable from classic force fields (energetics) and continuum models (friction tensors). A hierarchy of approaches of different complexity is proposed in this unified context, aimed primarily at the interpretation of magnetic resonance relaxation experiments. In particular, a model based on a harmonic internal Hamiltonian is discussed as a test case.

7.
J Phys Chem B ; 123(13): 2745-2755, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30839218

RESUMO

We report on progress toward improving NMR relaxation analysis in proteins in terms of the slowly relaxing local structure (SRLS) approach by developing a method that combines SRLS with molecular dynamics (MD) simulations. 15N-H bonds from the Rho GTPase binding domain of plexin-B1 are used as test case. We focus on the locally restricting/ordering potential of mean force (POMF), u(θ,φ), at the N-H site (θ and φ specify the orientation of the N-H bond in the protein). In SRLS, u(θ,φ) is expanded in the basis set of the real linear combinations of the Wigner rotation matrix elements with M = 0, D L,| K|(θ,φ). Because of limited data sensitivity, only the lowest ( L = 2) terms are preserved; this potential function is denoted by u(SRLS). In MD, the force-field-parametrized POMF is the potential, u(MD), defined in terms of the probability distribution, Peq(MD) ∝ exp(- u(MD)). Peq(MD), and subsequently u(MD), can be derived from the MD trajectory as histograms. One might contemplate utilizing u(MD) instead of u(SRLS); however, histograms cannot be used in SRLS analyses. Here, we approximate u(θ,φ) in terms of linear combinations of the D L,| K| functions with L = 1-4 and appropriate symmetry, denoted by u(DLK), and optimize the latter (via Peq) against u(MD). This yields for every N-H bond an analytical ordering potential, u(DLK-BEST), which exceeds u(SRLS) considerably in accuracy. u(DLK-BEST) can be used fixed in SRLS data fitting, thereby enabling the determination of additional parameters. This yields a substantially improved picture of structural dynamics, which is a significant benefit. The primary achievement of this work is to have employed for the first time MD data to derive a suitable (in terms of composition and symmetry) approximation to the SRLS POMF.

8.
J Comput Chem ; 40(4): 697-705, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30549075

RESUMO

We report on an extended hydrodynamic modeling of the friction tensorial properties of flexible molecules including all types of natural, Z-Matrix like, internal coordinates. We implement the new methodology by extending and updating the software DiTe [Barone et al. J. Comput. Chem. 30, 2 (2009)]. DiTe (DIffusion TEnsor) implements a hydrodynamic modeling of the generalized translational, rotational, and configurational friction and diffusion tensors of flexible molecules in which flexibility is described in terms of dihedral angles. The new tool, DiTe2, has been renewed to include also stretching and bending types of internal mobility. Furthermore, DiTe2 is able to calculate the friction and diffusion tensors along collective (or reaction) coordinates defined as linear combinations of the internal natural ones. A number of tests are reported to show the new features of DiTe2. As leitmotiv for the tests, the calmodulin protein is taken into consideration, described both at all-atom and coarse-grained levels. © 2018 Wiley Periodicals, Inc.

9.
Phys Chem Chem Phys ; 21(7): 3662-3668, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30417189

RESUMO

We show that under proper assumptions it is possible to estimate with good precision the principal values of the rotational diffusion tensor of proteins from the analysis of short (up to 2-3 ns) molecular dynamics trajectories. We apply this analysis to a few model cases: three polyalanine peptides (2, 5, and 10 aminoacids), the fragment B3 of protein G (GB3), the bovine pancreatic trypsin inhibitor (BPTI), the hen egg-white lysozyme (LYS), the B1 domain of plexin (PB1), and thrombin. The protocol is based on the analysis of the global angular momentum autocorrelation functions, complementing the standard approach based on rotational autocorrelation functions, which requires much longer trajectories. A comparison with values predicted by hydrodynamic modeling and available experimental data is presented.

10.
J Phys Chem B ; 122(8): 2287-2294, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29385337

RESUMO

Among biomolecules, carbohydrates are unique in that not only can linkages be formed through different positions, but the structures may also be branched. The trisaccharide ß-d-Glcp-(1→3)[ß-d-Glcp-(1→2)]-α-d-Manp-OMe represents a model of a branched vicinally disubstituted structure. A 13C site-specific isotopologue, with labeling in each of the two terminal glucosyl residues, enabled the acquisition of high-quality 13C NMR relaxation parameters, T1 and T2, and heteronuclear NOE, with standard deviations of ≤0.5%. For interpretation of the experimental NMR data, a diffusive chain model was used, in which the dynamics of the glycosidic linkages is coupled to the global reorientation motion of the trisaccharide. Brownian dynamics simulations relying on the potential of mean force at the glycosidic linkages were employed to evaluate spectral densities of the spin probes. Calculated NMR relaxation parameters showed a very good agreement with experimental data, deviating <3%. The resulting dynamics are described by correlation times of 196 and 174 ps for the ß-(1→2)- and ß-(1→3)-linked glucosyl residues, respectively, i.e., different and linkage dependent. Notably, the devised computational protocol was performed without any fitting of parameters.


Assuntos
Glicosídeos/química , Simulação de Dinâmica Molecular , Oligossacarídeos/química , Configuração de Carboidratos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13/normas , Padrões de Referência , Processos Estocásticos
11.
J Phys Chem Lett ; 8(10): 2236-2242, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28471190

RESUMO

The controversial nature of the fluorescent properties of carbon dots (CDs), ascribed either to surface states or to small molecules adsorbed onto the carbon nanostructures, is an unresolved issue. To date, an accurate picture of CDs and an exhaustive structure-property correlation are still lacking. Using two unconventional spectroscopic techniques, fluorescence correlation spectroscopy (FCS) and time-resolved electron paramagnetic resonance (TREPR), we contribute to fill this gap. Although electron micrographs indicate the presence of carbon cores, FCS reveals that the emission properties of CDs are based neither on those cores nor on molecular species linked to them, but rather on free molecules. TREPR provides deeper insights into the structure of carbon cores, where C sp2 domains are embedded within C sp3 scaffolds. FCS and TREPR prove to be powerful techniques, characterizing CDs as inherently heterogeneous systems, providing insights into the nature of such systems and paving the way to standardization of these nanomaterials.

12.
J Phys Chem B ; 121(17): 4379-4387, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28422504

RESUMO

We address the interpretation, via an integrated computational approach, of the experimental continuous-wave electron paramagnetic resonance (cw-EPR) spectra of a complete set of conformationally highly restricted, stable 310-helical peptides from hexa- to nonamers, each bis-labeled with nitroxide radical-containing TOAC (4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-4-carboxylic acid) residues. The usefulness of TOAC for this type of analysis has been shown already to be due to its cyclic piperidine side chain, which is rigidly connected to the peptide backbone α-carbon. The TOAC α-amino acids are separated by two, three, four, and five intervening residues. This set of compounds has allowed us to modulate both the radical···radical distance and the relative orientation parameters. To further validate our conclusion, a comparative analysis has been carried out on three singly TOAC-labeled peptides of similar main-chain length.


Assuntos
Óxidos N-Cíclicos/química , Óxidos de Nitrogênio/química , Peptídeos/química , Teoria Quântica , Espectroscopia de Ressonância de Spin Eletrônica , Marcadores de Spin
13.
J Phys Chem B ; 121(14): 3007-3015, 2017 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-28281763

RESUMO

We report on a new method for determining function-related conformational entropy changes in proteins. Plexin-B1 RBD dimerization serves as example, and internally mobile N-H bonds serve as probes. Sk (entropy in units of kBT) is given by -∫(PeqlnPeq)dΩ, where Peq = exp(-u) is the probability density for probe orientation, and u the local potential. Previous slowly relaxing local structure (SRLS) analyses of 15N-H relaxation in proteins determined linear combinations of D002(Ω) and (D022(Ω) + D0-22(Ω)) (D0KL(Ω) represents a Wigner rotation matrix element in uniaxial local medium) as "best-fit" form of u. SRLS also determined the "best-fit" orientation of the related ordering tensor. On the basis of this information the coefficients (in the linear combination) of the terms specified above are determined with molecular dynamics (MD) simulations. With the explicit expression for u thus in hand, Sk is calculated. We find that in general Sk decreases, i.e., the local order increases, upon plexin-B1 RBD dimerization. The largest decrease in Sk occurs in the helices α1 and α2, followed by the α2/ß6 turn. Only the relatively small peripheral ß2 strand, ß2/α1 turn, and L3 loop become more disordered. That α-helices dominate ΔSk = Sk(dimer) - Sk(monomer), a few peripheral outliers partly counterbalance the overall decrease in Sk, and the probability density function, Peq, has rhombic symmetry given that the underlying potential function, u, has rhombic symmetry, are interesting features. We also derive S2 (the proxy of u in the simple "model-free (MF)" limit of SRLS) with MD. Its conversion into a potential requires assumptions and adopting a simple axial form of u. Ensuing ΔSk(MF) profiles are u-dependent and differ from ΔSk(SRLS). A method that provides consistent, general, and accurate Sk, atomistic/mesoscopic in nature, has been developed. Its ability to provide new insights in protein research has been illustrated.


Assuntos
Entropia , Simulação de Dinâmica Molecular , Proteínas do Tecido Nervoso/química , Ressonância Magnética Nuclear Biomolecular , Multimerização Proteica , Receptores de Superfície Celular/química , Humanos , Isótopos de Nitrogênio , Conformação Proteica
14.
Biochemistry ; 55(28): 3984-94, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27347732

RESUMO

Thrombin exists as an ensemble of active (E) and inactive (E*) conformations that differ in their accessibility to the active site. Here we show that redistribution of the E*-E equilibrium can be achieved by perturbing the electrostatic properties of the enzyme. Removal of the negative charge of the catalytic Asp102 or Asp189 in the primary specificity site destabilizes the E form and causes a shift in the 215-217 segment that compromises substrate entrance. Solution studies and existing structures of D102N document stabilization of the E* form. A new high-resolution structure of D189A also reveals the mutant in the collapsed E* form. These findings establish a new paradigm for the control of the E*-E equilibrium in the trypsin fold.


Assuntos
Eletricidade Estática , Trombina/química , Biocatálise , Cristalografia por Raios X , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Trombina/metabolismo
15.
Phys Chem Chem Phys ; 18(4): 3086-96, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26741055

RESUMO

The monosaccharide L-rhamnose is common in bacterial polysaccharides and the disaccharide α-L-Rhap-α-(1 → 2)-α-L-Rhap-OMe represents a structural model for a part of Shigella flexneri O-antigen polysaccharides. Utilization of [1'-(13)C]-site-specific labeling in the anomeric position at the glycosidic linkage between the two sugar residues facilitated the determination of transglycosidic NMR (3)JCH and (3)JCC coupling constants. Based on these spin-spin couplings the major state and the conformational distribution could be determined with respect to the ψ torsion angle, which changed between water and dimethyl sulfoxide (DMSO) as solvents, a finding mirrored by molecular dynamics (MD) simulations with explicit solvent molecules. The (13)C NMR spin relaxation parameters T1, T2, and heteronuclear NOE of the probe were measured for the disaccharide in DMSO-d6 at two magnetic field strengths, with standard deviations ≤1%. The combination of MD simulation and a stochastic description based on the diffusive chain model resulted in excellent agreement between calculated and experimentally observed (13)C relaxation parameters, with an average error of <2%. The coupling between the global reorientation of the molecule and the local motion of the spin probe is deemed essential if reproduction of NMR relaxation parameters should succeed, since decoupling of the two modes of motion results in significantly worse agreement. Calculation of (13)C relaxation parameters based on the correlation functions obtained directly from the MD simulation of the solute molecule in DMSO as solvent showed satisfactory agreement with errors on the order of 10% or less.


Assuntos
Dimetil Sulfóxido/química , Glicosídeos/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Conformação Molecular , Simulação de Dinâmica Molecular , Processos Estocásticos
16.
Phys Chem Chem Phys ; 17(12): 8038-52, 2015 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-25723739

RESUMO

In this work we show that a non-equilibrium statistical tool based on Jarzynski's equality (JE) can be applied to achieve a sufficiently accurate mapping of the torsion free energy, bond-by-bond, for an alkyl thiol ligand tethered to a gold surface and sensing the presence of the surrounding cluster of similar chains. The strength of our approach is the employment of a strategy to let grow the internal energetics of the whole system (namely, the "energy morphing" stage recently presented by us in J. Comput. Chem., 2014, 35, 1865-1881) before initiating the rotational steering, which yields accurate results in terms of statistical uncertainties and bias on the free energy profiles. The work is mainly methodological and illustrates the feasibility of this kind of inspection on nanoscale molecular clusters with conformational flexibility. The outcomes for the archetype of self-assembled-monolayers considered here, a regular pattern of 10-carbon alkyl thiols on an ideal gold surface, give information on the conformational mobility of the ligands. Notably, such information is unlikely to be obtained by means of standard equilibrium techniques or by conventional molecular dynamics simulations.

17.
Phys Chem Chem Phys ; 17(3): 1966-79, 2015 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-25475171

RESUMO

We illustrate how the Jarzynski equality (JE), which is the progenitor of non-equilibrium methods aimed at constructing free energy landscapes for molecular-sized fluctuating systems subjected to steered transformations, can be applied to derive equations of state for bulk systems. The key-step consists of physically framing the computational strategy of "total energy morphing", recently presented by us as an efficient implementation of the JE [M. Zerbetto, A. Piserchia, D. Frezzato, J. Comput. Chem., 2014, 35, 1865-1881], in terms of build-up of the real thermodynamic state of a bulk material from the corresponding ideal state, in which the particles are non-interacting. In this context, the JE machinery yields the excess free energy versus suitably chosen controlled state variables, whose thermodynamic derivatives eventually lead to the equation of state. As an explanatory case study, we apply the methodology to derive the equation of state of gaseous methane by constructing the Helmholtz free energy versus the particle density (at fixed temperature) and then evaluating the thermodynamic derivative with respect to the volume. In our intent, this "old-style" work on gaseous methane should open the way for the investigation of thermodynamics of extended systems via non-equilibrium methods.

18.
J Comput Chem ; 35(25): 1865-81, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25087652

RESUMO

In this communication, we present the Jarzynski's Equality FREe Energy (JEFREE) library, an efficient and easy-to-use C++ library targeted to the calculation of the free energy profile along a selected generalized coordinate of a system, within the framework of the nonequilibrium steered transformations as introduced by Jarzynski [Phys. Rev. E, 1997, 56, 5018]. JEFREE can be readily integrated into any code, since both C and FORTRAN wrappers have been developed, and easily customizable by a user thanks to the object-oriented programming paradigm offered by the C++ language. Also, JEFREE implements the novel idea of making a total "morphing" of the system energy landscape before initiating the proper steering stage. This proves to be an efficient mean to overtake the problematic sampling of the initial equilibrium state when the number of degrees of freedom is high and the landscape owns many local minima separated by large energy barriers. The calculation of the free energy profile for the rotation along torsion angles in alkyl chains is presented as an example of application of our tool.

19.
Chemphyschem ; 15(2): 310-9, 2014 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-24265124

RESUMO

Time-resolved fluorescence and transient absorption experiments uncover a distinct change in the relaxation dynamics of the homo-dimer formed by two 2,5-bis[1-(4-N-methylpyridinium)ethen-2-yl)]-N-methylpyrrole ditriflate (M) units linked by a short alkyl chain when compared to that of the monomer M. Fluorescence decay traces reveal characteristic decay times of 1.1 ns and 210 ps for M and the dimer, respectively. Transient absorption spectra in the spectral range of 425-1050 nm display similar spectral features for both systems, but strongly differ in the characteristic relaxation times gathered from a global fit of the experimental data. To rationalize the data we propose that after excitation of the dimer the energy localizes on one M branch and then decays to a dark state, peculiar only of the dimer. This dark state relaxes to the ground state within 210 ps through non-radiative relaxation. The nature of the dark state is discussed in relation to different possible photophysical processes such as excimer formation and charge transfer between the two M units. Anisotropy decay traces of the probe-beam differential transmittance of M and the dimer fall on complete different time scales as well. The anisotropy decay for M is satisfactorily ascribed to rotational diffusion in DMSO, whereas for the dimer it occurs on a faster time scale and is likely caused by energy-transfer processes between the two monomer M units.

20.
J Phys Chem B ; 117(1): 174-84, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23214953

RESUMO

We investigate picosecond­nanosecond dynamics of the Rho-GTPase Binding Domain (RBD) of plexin-B1, which plays a key role in plexin-mediated cell signaling. Backbone 15N relaxation data of the dimeric RBD are analyzed with the model-free (MF) method, and with the slowly relaxing local structure/molecular dynamics (SRLS-MD) approach. Independent analysis of the MD trajectories, based on the MF paradigm, is also carried out. MF is a widely popular and simple method, SRLS is a general approach, and SRLS-MD is an integrated approach we developed recently. Corresponding parameters from the RBD dimer, a previously studied RBD monomer mutant, and the previously studied complex of the latter with the GTPase Rac1, are compared. The L2, L3, and L4 loops of the plexin-B1 RBD are involved in interactions with other plexin domains, GTPase binding, and RBD dimerization, respectively. Peptide groups in the loops of both the monomeric and dimeric RBD are found to experience weak and moderately asymmetric local ordering centered approximately at the C(i­1)(α)­C(i)(α) axes, and nanosecond backbone motion. Peptide groups in the α-helices and the ß-strands of the dimer (the ß-strands of the monomer) experience strong and highly asymmetric local ordering centered approximately at the C(i­1)(α)­C(i)(α) axes (N­H bonds). N­H fluctuations occur on the picosecond time scale. An allosteric pathway for GTPase binding, providing new insights into plexin function, is delineated.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Simulação de Dinâmica Molecular , Proteínas do Tecido Nervoso/química , Proteínas/química , Receptores de Superfície Celular/química , Proteínas rho de Ligação ao GTP/química , Regulação Alostérica , Dimerização , Isótopos de Nitrogênio , Prótons
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