Molecular Dynamics Simulations Of Lysozyme Research Articles

Quasiharmonic analysis of protein energy landscapes from pressure-temperature molecular dynamics simulations

Positional fluctuations of an atom in a protein can be described as motion in an effective local energy minimum created by the surrounding protein atoms. The dependence of atomic fluctuations on both temperature (T) and pressure (P) has been used to probe the nature of these minima, which are generally described as harmonic in experiments such as x-ray crystallography and neutron scattering. Here, a quasiharmonic analysis method is presented in which the P-T dependence of atomic fluctuations is in terms of an intrinsic isobaric thermal expansivity αP and an intrinsic isothermal compressibility κT. The method is tested on previously reported mean-square displacements from P-T molecular dynamics simulations of lysozyme, which were interpreted to have a pressure-independent dynamical transition Tg near 200 K and a change in the pressure dependence near 480 MPa. Our quasiharmonic analysis of the same data shows that the P-T dependence can be described in terms of αP and κT where below Tg, the temperature dependence is frozen at the Tg value. In addition, the purported transition at 480 MPa is reinterpreted as a consequence of the pressure dependence of Tg and the quasiharmonic frequencies. The former also indicates that barrier heights between substates are pressure dependent in these data. Furthermore, the insights gained from this quasiharmonic analysis, which was of the energy landscape near the native state of a protein, suggest that similar analyses of other simulations may be useful in understanding such phenomena as pressure-induced protein unfolding.

Interaction of arginine, lysine, and guanidine with surface residues of lysozyme: implication to protein stability

Additives are widely used to suppress aggregation of therapeutic proteins. However, the molecular mechanisms of effect of additives to stabilize proteins are still unclear. To understand this, we herein perform molecular dynamics simulations of lysozyme in the presence of three commonly used additives: arginine, lysine, and guanidine. These additives have different effects on stability of proteins and have different structures with some similarities; arginine and lysine have aliphatic side chain, while arginine has a guanidinium group. We analyze atomic contact frequencies to study the interactions of the additives with individual residues of lysozyme. Contact coefficient, quantified from contact frequencies, is helpful in analyzing the interactions with the guanidine groups as well as aliphatic side chains of arginine and lysine. Strong preference for contacts to the additives (over water) is seen for the acidic followed by polar and the aromatic residues. Further analysis suggests that the hydration layer around the protein surface is depleted more in the presence of arginine, followed by lysine and guanidine. Molecular dynamics simulations also reveal that the internal dynamics of protein, as indicated by the lifetimes of the hydrogen bonds within the protein, changes depending on the additives. Particularly, we note that the side-chain hydrogen-bonding patterns within the protein differ with the additives, with several side-chain hydrogen bonds missing in the presence of guanidine. These results collectively indicate that the aliphatic chain of arginine and lysine plays a critical role in the stabilization of the protein.

Molecular Dynamics Simulation of Lysozyme Adsorption/Desorption on Hydrophobic Surfaces

In this work, we present a series of fully atomistic molecular dynamics (MD) simulations to study lysozyme's orientation-dependent adsorption on polyethylene (PE) surface in explicit water. The simulations show that depending on the orientation of the initial approach to the surface the protein may adsorb or bounce from the surface. The protein may completely leave the surface or reorient and approach the surface resulting in adsorption. The success of the trajectory to adsorb on the surface is the result of different competing interactions, including protein-surface interactions and the hydration of the protein and the hydrophobic PE surface. The difference in the hydration of various protein sites affects the protein's orientation-dependent behavior. Side-on orientation is most likely to result in adsorption as the protein-surface exhibits the strongest attraction. However, adsorption can also happen when lysozyme's longest axis is tilted on the surface if the protein-surface interaction is large enough to overcome the energy barrier that results from dehydrating both the protein and the surface. Our study demonstrates the significant role of dehydration process on hydrophobic surface during protein adsorption.

Surface Hydration Amplifies Single-Well Protein Atom Diffusion Propagating into the Macromolecular Core

The effect of surface hydration water on internal protein motion is of fundamental interest in molecular biophysics. Here, by decomposing the picosecond to nanosecond atomic motion in molecular dynamics simulations of lysozyme at different hydration levels into three components--localized single-well diffusion, methyl group rotation, and nonmethyl jumps--we show that the effect of surface hydration is mainly to increase the volume of the localized single-well diffusion. These diffusive motions are coupled in such a way that the hydration effect propagates from the protein surface into the dry core.

Communication: A minimal model for the diffusion-relaxation backbone dynamics of proteins

We present a model for the local diffusion-relaxation dynamics of the C(α)-atoms in proteins describing both the diffusive short-time dynamics and the asymptotic long-time relaxation of the position autocorrelation functions. The relaxation rate spectra of the latter are represented by shifted gamma distributions, where the standard gamma distribution describes anomalous slow relaxation in macromolecular systems of infinite size and the shift accounts for a smallest local relaxation rate in macromolecules of finite size. The resulting autocorrelation functions are analytic for any time t ≥ 0. Using results from a molecular dynamics simulation of lysozyme, we demonstrate that the model fits the position autocorrelation functions of the C(α)-atoms exceptionally well and reveals moreover a strong correlation between the residue's solvent-accessible surface and the fitted model parameters.

Structural variability and the incoherent addition of scattered intensities in single-particle diffraction

X-ray lasers may allow structural studies on single particles and biomolecules without crystalline periodicity in the samples. We examine here the effect of sample dynamics as a source of structural heterogeneity on the resolution of the reconstructed image of a small protein molecule. Structures from molecular-dynamics simulations of lysozyme were sampled and aligned. These structures were then used to calculate diffraction patterns corresponding to different dynamic states. The patterns were incoherently summed and the resulting data set was phased using the oversampling method. Reconstructed images of hydrated and dehydrated lysozyme gave resolutions of 3.7 A and 7.6 A , respectively. These are significantly worse than the root-mean-square deviation of the hydrated ( 2.7 A for all atoms and 1.45 A for C-alpha positions) or dehydrated ( 3.7 A for all atoms and 2.5 A for C-alpha positions) structures. The noise introduced by structural dynamics and incoherent addition of dissimilar structures restricts the maximum resolution to be expected from direct image reconstruction of dynamic systems. A way of potentially reducing this effect is by grouping dynamic structures into distinct structural substates and solving them separately.

Picosecond fluctuating protein energy landscape mapped by pressure–temperature molecular dynamics simulation

Microscopic statistical pressure fluctuations can, in principle, lead to corresponding fluctuations in the shape of a protein energy landscape. To examine this, nanosecond molecular dynamics simulations of lysozyme are performed covering a range of temperatures and pressures. The well known dynamical transition with temperature is found to be pressure-independent, indicating that the effective energy barriers separating conformational substates are not significantly influenced by pressure. In contrast, vibrations within substates stiffen with pressure, due to increased curvature of the local harmonic potential in which the atoms vibrate. The application of pressure is also shown to selectively increase the damping of the anharmonic, low-frequency collective modes in the protein, leaving the more local modes relatively unaffected. The critical damping frequency, i.e., the frequency at which energy is most efficiently dissipated, increases linearly with pressure. The results suggest that an invariant description of protein energy landscapes should be subsumed by a fluctuating picture and that this may have repercussions in, for example, mechanisms of energy dissipation accompanying functional, structural, and chemical relaxation.

Molecular dynamics simulations of lysozyme in water/sugar solutions

Structural and dynamical properties of the solvent at the protein/solvent interface have been investigated by molecular dynamics simulations of lysozyme in trehalose, maltose and sucrose solutions. Results are discussed in the framework of the bioprotection phenomena. The analysis of the relative concentration of water oxygen atoms around lysozyme suggests that lysozyme is preferentially hydrated. When comparing the three sugars, trehalose is seen more excluded than maltose and sucrose. The preferential exclusion of sugars from the protein surface induces some differences in the behavior of trehalose and maltose, particularly at 50 and 60 wt% concentrations, that are not observed experimentally in binary sugar/mixtures. The dynamical slowing down of the solvent is suggested to mainly arise from the homogeneity of the water/sugar matrices controlled by the percolation of the sugar hydrogen bonds networks. Furthermore, lysozyme strongly increases relaxation times of solvent molecules at the protein/solvent interface.

Effect of pressure on the conformation of proteins. A molecular dynamics simulation of lysozyme

The effect of pressure on the structure and mobility of lysozyme was studied by molecular dynamics computer simulation at 1 and 3 kbar (1 atm = 1.01325 bar = 101.325 kPa). The results have good agreement with the available experimental data, allowing the analysis of other features of the effect of pressure on the protein solution. The studies of mobility show that although the general mobility is restricted under pressure this is not true for some particular residues. From the analysis of secondary structure along the trajectories it is observed that the conformation under pressure is more stable, suggesting that pressure acts as a ‘conformer selector’ on the protein. The difference in solvent-accessed surface (SAS) with pressure shows a clear inversion of the hydrophilic/hydrophobic SAS ratio, which consequently shows that the hydrophobic interaction is considerably weaker under high hydrostatic pressure conditions.

Water rotational relaxation and diffusion in hydrated lysozyme.

This paper is concerned with the dynamics of water around a small globular protein. Dipolar second-rank relaxation time and diffusion properties of surface water were computed by extensive molecular dynamics simulations of lysozyme in water which lasted a total of 28 ns. Our results indicate that the rotational relaxation of water in the vicinity of lysozyme is 3-7 times slower than that in the bulk depending on how the hydration shell is defined in the calculation. We have also verified that the dynamics of water translational diffusion in the vicinity of lysozyme have retardations similar to rotational relaxation. This is a common assumption in nuclear magnetic relaxation dispersion (NMRD) studies to derive residence times. In contrast to bulk water dynamics, surface water is in a dispersive diffusion regime or subdiffusion. Very good agreement of dipolar second-rank relaxation time with NMRD estimates is obtained by using appropriate dimensions of the hydration shell. Although our computed second-rank dipolar retardations are independent of the water model, SPC/E describes more realistically the time scale of the water dynamics around lysozyme than does TIP3P.

SASSIM: a method for calculating small-angle X-ray and neutron scattering and the associated molecular envelope from explicit-atom models of solvated proteins.

A method is presented to calculate efficiently small-angle neutron and X-ray solution scattering intensities from explicit-atom models of macromolecules and the surrounding solvent. The method is based on a multipole expansion of the scattering amplitude. It is particularly appropriate for extensive configurational averaging, as is required for calculations based on computer-simulation results. In test calculations, excellent agreement with experiment is found between neutron and X-ray scattering profiles calculated from a molecular-dynamics simulation of lysozyme in water. The question of definition of the protein surface is also addressed. For comparison with the continuum model, an analytical envelope around the protein is defined in terms of spherical harmonics and is calculated using a Lebedev grid. The analytical surface thus defined is shown to reproduce well the scattering profile calculated from the explicit-atom model of the protein.

Internal motional averaging and three-dimensional structure determination by nuclear magnetic resonance

Dynamic averaging effects from internal motions on interproton distances estimated from nuclear Overhauser effects (NOE) are determined by using a molecular dynamics simulation of lysozyme. Generalized order parameters measuring angular averaging and radial averaging parameters are calculated. The product of these two parameters describes the full averaging effects on cross-relaxation. Analysis of 2778 non-methyl NOE interactions from the protein interior and surface indicates that distances estimated by assuming a rigid molecule have less than 10% error for 89% of the NOE interactions. However, analysis of 1854 methyl interactions found that only 68% of the distances estimated from cross-relaxation rates would have less than 10% error. Qualitative evaluation of distances according to strong, medium and weak NOE intensities, when used to define only the upper bound for interproton separation, would misassign less than 1% of the distance constraints because of motional averaging. Internal motions do not obscure the identification of secondary structure, although some instances of significant averaging effects were found for interactions in α-helical regions. Interresidue NOEs for amino acids more than three residues apart in the primary sequence are more extensively averaged than intraresidue or shortrange interresidue NOEs. Intraresidue interactions exhibit a greater degree of angular averaging than those involving interresidue proton pairs. An internal motion does not equally affect all NOE interactions for a particular proton. Thus, incorporation of averaging parameters in nuclear magnetic resonance structure determination procedures must be made on a proton-pair-wise basis. On the basis of the motional averaging results, particular fixed-distance proton pairs in proteins are suggested for use as distance references. A small percentage of NOE pairs localized to three regions of the protein exhibit extreme averaging effects from internal motions. The regions and types of motions involved are described.

Solvent effects on protein motion and protein effects on solvent motion: Dynamics of the active site region of lysozyme

The stochastic boundary molecular dynamics methodology is applied to the active site of the enzyme lysozyme. A comparison is made of in vacuo dynamics results from the stochastic boundary method and a full conventional molecular dynamics simulation of lysozyme. Excellent agreement between the two approaches is obtained. The influence of solvent on the residues in the active site region is explored and it is shown that both the structure and dynamics are affected. Of particular importance for the structure of the protein is the solvation of polar residues and the stabilization of like-charged ion pairs. The magnitude of the fluctuations is only slightly altered by the solvent; the overall increase in the root-mean-square fluctuations, relative to the vacuum run, is 11%. The solvent effect on dynamical properties is found not to be simply related to the solvent viscosity. Both the solvent exposure and dynamic aspects of protein-solvent interactions, including the relative time scales of the motions, are shown to play a role. The effects of the protein on solvent dynamics and structure are also observed to be significant. The solvent molecules around atoms in charged, polar and apolar side-chains show markedly different diffusion coefficients as well as exhibiting different solvation structures. One key example is the water around apolar groups, which is much less mobile than bulk water, or water solvating polar groups.

ChemInform Abstract: MOTIONAL AVERAGING OF PROTON NUCLEAR OVERHAUSER EFFECTS IN PROTEINS. PREDICTIONS FROM A MOLECULAR DYNAMICS SIMULATION OF LYSOZYME

Chemischer InformationsdienstVolume 15, Issue 27 Physical Organic Chemistry ChemInform Abstract: MOTIONAL AVERAGING OF PROTON NUCLEAR OVERHAUSER EFFECTS IN PROTEINS. PREDICTIONS FROM A MOLECULAR DYNAMICS SIMULATION OF LYSOZYME E. T. OLEJNICZAK, E. T. OLEJNICZAKSearch for more papers by this authorC. M. DOBSON, C. M. DOBSONSearch for more papers by this authorM. KARPLUS, M. KARPLUSSearch for more papers by this authorR. M. LEVY, R. M. LEVYSearch for more papers by this author E. T. OLEJNICZAK, E. T. OLEJNICZAKSearch for more papers by this authorC. M. DOBSON, C. M. DOBSONSearch for more papers by this authorM. KARPLUS, M. KARPLUSSearch for more papers by this authorR. M. LEVY, R. M. LEVYSearch for more papers by this author First published: July 3, 1984 https://doi.org/10.1002/chin.198427055AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume15, Issue27July 3, 1984 RelatedInformation

Motional averaging of proton nuclear Overhauser effects in proteins. Predictions from a molecular dynamics simulation of lysozyme

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMotional averaging of proton nuclear Overhauser effects in proteins. Predictions from a molecular dynamics simulation of lysozymeE. T. Olejniczak, C. M. Dobson, M. Karplus, and R. M. LevyCite this: J. Am. Chem. Soc. 1984, 106, 7, 1923–1930Publication Date (Print):April 1, 1984Publication History Published online1 May 2002Published inissue 1 April 1984https://doi.org/10.1021/ja00319a004RIGHTS & PERMISSIONSArticle Views240Altmetric-Citations107LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (927 KB) Get e-Alerts Get e-Alerts

Fluorescence depolarization of tryptophan residues in proteins: a molecular dynamics study.

A molecular dynamics simulation of lysozyme is used to examine the fluorescence depolarization of tryptophan residues on the picosecond time scale. The calculated time dependence of fluorescence emission anisotropy for the six tryptophans in lysozyme exhibits a wide variety of motional behavior that should correspond to the range expected more generally for tryptophan residues in proteins. It is found that some tryptophans are highly mobile with a large fluorescence anisotropy decay on the picosecond time scale while others are essentially rigid due to the presence of the protein matrix. Further, it is demonstrated that correlations among the internal degrees of freedom (e.g., dihedral angles) play an important role in the observed decay behavior; this suggests that care has to be used in interpreting experimental results in terms of simple motional models. Because the available experimental time resolution is limited to the nanosecond time scale, only the effective zero-time anisotropy can be compared with the calculated values. The results suggest that the study of fluorescence depolarization with femtosecond lasers would provide new insights into the short time dynamics of amino acid side chains in proteins.