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PubMed2002

A fast pairwise evaluation of molecular surface area.

A fast and general analytical approach was developed for the calculation of the approximate van der Waals and solvent-accessible surface areas. The method is based on three basic ideas: the use of the Lorentz transformation formula, a rigid-geometry approximation, and a single fitting parameter that can be refitted on the fly during a simulation. The Lorentz transformation equation is used for the summation of the areas of an atom buried by its neighboring contacting atoms, and implies that a sum of the buried pairwise areas cannot be larger than the surface area of the isolated spherical atom itself. In a rigid-geometry approximation we numerically calculate and keep constant the surface of each atom buried by the atoms involved in 1-2 and 1-3 interactions. Only the contributions from the nonbonded atoms (1-4 and higher interactions) are considered in terms of the pairwise approximation. The accuracy and speed of the method is competitive with other pairwise algorithms. A major strength of the method is the ease of parametrization.

Journal Article↗

PubMed2002

Modern protein force fields behave comparably in molecular dynamics simulations.

Several molecular dynamics simulations were performed on three proteins--bovine apo-calbindin D9K, human interleukin-4 R88Q mutant, and domain IIA of bacillus subtilis glucose permease--with each of the AMBER94, CHARMM22, and OPLS-AA force fields as implemented in CHARMM. Structural and dynamic properties such as solvent-accessible surface area, radius of gyration, deviation from their respective experimental structures, secondary structure, and backbone order parameters are obtained from each of the 2-ns simulations for the purpose of comparing the protein portions of these force fields. For one of the proteins, the interleukin-4 mutant, two independent simulations were performed using the CHARMM22 force field to gauge the sensitivity of some of these properties to the specific trajectory. In general, the force fields tested performed remarkably similarly with differences on the order of those found for the two independent trajectories of interleukin-4 with CHARMM22. When all three proteins are considered together, no force field showed any consistent trend in variations for most of the properties monitored in the study.

Animals↗

PubMed2001

Molecular mechanics and dynamics of biomolecules using a solvent continuum model.

An easy implementation of molecular mechanics and molecular dynamics simulation using a continuum solvent model is presented that is particularly suitable for biomolecular simulations. The computation of solvation forces is made using the linear Poisson-Boltzmann equation (polar contribution) and the solvent-accessible surface area approach (nonpolar contribution). The feasibility of the methodology is demonstrated on a small protein and a small DNA hairpin. Although the parameters employed in this model must be refined to gain reliability, the performance of the method, with a standard choice of parameters, is comparable with results obtained by explicit water simulations. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1830-1842, 2001

Journal Article↗

PubMed2001

Effective atom volumes for implicit solvent models: comparison between Voronoi volumes and minimum fluctuation volumes.

An essential element of implicit solvent models, such as the generalized Born method, is a knowledge of the volume associated with the individual atoms of the solute. Two approaches for determining atomic volumes for the generalized Born model are described; one is based on Voronoi polyhedra and the other, on minimizing the fluctuations in the overall volume of the solute. Volumes to be used with various parameter sets for protein and nucleic acids in the CHARMM force field are determined from a large set of known structures. The volumes resulting from the two different approaches are compared with respect to various parameters, including the size and solvent accessibility of the structures from which they are determined. The question of whether to include hydrogens in the atomic representation of the solute volume is examined. Copyright 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1857-1879, 2001

Journal Article↗

PubMed2002

Computational alanine scanning of the 1:1 human growth hormone-receptor complex.

The MM-PBSA (Molecular Mechanics-Poisson-Boltzmann surface area) method was applied to the human Growth Hormone (hGH) complexed with its receptor to assess both the validity and the limitations of the computational alanine scanning approach. A 400-ps dynamical trajectory of the fully solvated complex was simulated at 300 K in a 101 A x 81 A x 107 A water box using periodic boundary conditions. Long-range electrostatic interactions were treated with the particle mesh Ewald (PME) summation method. Equally spaced snapshots along the trajectory were chosen to compute the binding free energy using a continuum solvation model to calculate the electrostatic desolvation free energy and a solvent-accessible surface area approach to treat the nonpolar solvation free energy. Computational alanine scanning was performed on the same set of snapshots by mutating the residues in the structural epitope of the hormone and the receptor to alanine and recomputing the deltaGbinding. To further investigate a particular structure, a 200-ps dynamical trajectory of an R43A hormone-receptor complex was simulated. By postprocessing a single trajectory of the wild-type complex, the average unsigned error of our calculated deltadeltaGbinding is approximately1 kcal/mol for the alanine mutations of hydrophobic residues and polar/charged residues without buried salt bridges. When residues involved in buried salt bridges are mutated to alanine, it is demonstrated that a separate trajectory of the alanine mutant complex can lead to reasonable agreement with experimental results. Our approach can be extended to rapid screening of a variety of possible modifications to binding sites.

Alanine↗

PubMed2002

Application of the frozen atom approximation to the GB/SA continuum model for solvation free energy.

The generalized Born/surface area (GB/SA) continuum model for solvation free energy is a fast and accurate alternative to using discrete water molecules in molecular simulations of solvated systems. However, computational studies of large solvated molecular systems such as enzyme-ligand complexes can still be computationally expensive even with continuum solvation methods simply because of the large number of atoms in the solute molecules. Because in such systems often only a relatively small portion of the system such as the ligand binding site is under study, it becomes less attractive to calculate energies and derivatives for all atoms in the system. To curtail computation while still maintaining high energetic accuracy, atoms distant from the site of interest are often frozen; that is, their coordinates are made invariant. Such frozen atoms do not require energetic and derivative updates during the course of a simulation. Herein we describe methodology and results for applying the frozen atom approach to both the generalized Born (GB) and the solvent accessible surface area (SASA) parts of the GB/SA continuum model for solvation free energy. For strictly pairwise energetic terms, such as the Coulombic and van-der-Waals energies, contributions from pairs of frozen atoms can be ignored. This leaves energetic differences unaffected for conformations that vary only in the positions of nonfrozen atoms. Due to the nonlocal nature of the GB analytical form, however, excluding such pairs from a GB calculation leads to unacceptable inaccuracies. To apply a frozen-atom scheme to GB calculations, a buffer region within the frozen-atom zone is generated based on a user-definable cutoff distance from the nonfrozen atoms. Certain pairwise interactions between frozen atoms in the buffer region are retained in the GB computation. This allows high accuracy in conformational GB comparisons to be maintained while achieving significant savings in computational time compared to the full (nonfrozen) calculation. A similar approach for using a buffer region of frozen atoms is taken for the SASA calculation. The SASA calculation is local in nature, and thus exact SASA energies are maintained. With a buffer region of 8 A for the frozen-atom cases, excellent agreement in differences in energies for three different conformations of cytochrome P450 with a bound camphor ligand are obtained with respect to the nonfrozen cases. For various minimization protocols, simulations run 2 to 10.5 times faster and memory usage is reduced by a factor of 1.5 to 5. Application of the frozen atom method for GB/SA calculations thus can render computationally tractable biologically and medically important simulations such as those used to study ligand-receptor binding conformations and energies in a solvated environment.

Macromolecular Substances↗

PubMed2004

Large-scale molecular dynamics simulations of HLA-A*0201 complexed with a tumor-specific antigenic peptide: can the alpha3 and beta2m domains be neglected?

Large-scale massively parallel molecular dynamics (MD) simulations of the human class I major histocompatibility complex (MHC) protein HLA-A*0201 bound to a decameric tumor-specific antigenic peptide GVYDGREHTV were performed using a scalable MD code on high-performance computing platforms. Such computational capabilities put us in reach of simulations of various scales and complexities. The supercomputing resources available for this study allow us to compare directly differences in the behavior of very large molecular models; in this case, the entire extracellular portion of the peptide-MHC complex vs. the isolated peptide binding domain. Comparison of the results from the partial and the whole system simulations indicates that the peptide is less tightly bound in the partial system than in the whole system. From a detailed study of conformations, solvent-accessible surface area, the nature of the water network structure, and the binding energies, we conclude that, when considering the conformation of the alpha1-alpha2 domain, the alpha3 and beta2m domains cannot be neglected.

Algorithms↗

PubMed2005

Absolute free energies of binding of peptide analogs to the HIV-1 protease from molecular dynamics simulations.

The constants of binding of five peptide analogs to the active site of the HIV-1 aspartic-protease are calculated based on a novel sampling scheme that is efficient and does not introduce any approximations in addition to the energy function used to describe the system. The results agree with experiments. The squared correlation coefficient of the calculated vs. the measured values is 0.79. The sampling scheme consists of a series of molecular dynamics integrations with biases. The biases are selected based on an estimate of the probability density function of the system in a way to explore the conformational space and to reduce the statistical error in the calculated binding constants. The molecular dynamics integrations are done with a vacuum potential using a short cutoff scheme. To estimate the probability density of the simulated system, the results of the molecular dynamics integrations are combined using an extension of the weighted histogram analysis method (C. Bartels, Chem. Phys. Letters 331 (2000) 446-454). The probability density of the solvated ligand-protein system is obtained by applying a correction for the use of the short cutoffs in the simulations and by taking into account solvation with an electrostatic term and a hydrophobic term. The electrostatic part of the solvation is determined by finite difference Poisson-Boltzmann calculations; the hydrophobic part of the solvation is set proportional to the solvent accessible surface area. Setting the hydrophobic surface tension parameter equal to 8 mol(-1) K(-1) A(-2), absolute binding constants are in the muM to nM range. This is in agreement with experiments. The standard errors determined from eight repeated binding constant determinations are a factor of 14 to 411. A single determination of a binding constant is done with 499700 steps of molecular dynamics integration and 4500 finite difference Poisson-Boltzmann calculations. The simulations can be analyzed with respect to conformational changes of the active site of the HIV-1 protease or the ligands upon binding and provide information that complements experiments and can be used in the drug development process.

Algorithms↗

PubMed2006

The effect of box shape on the dynamic properties of proteins simulated under periodic boundary conditions.

The effect of the box shape on the dynamic behavior of proteins simulated under periodic boundary conditions is evaluated. In particular, the influence of simulation boxes defined by the near-densest lattice packing (NDLP) in conjunction with rotational constraints is compared to that of standard box types without these constraints. Three different proteins of varying size, shape, and secondary structure content were examined in the study. The statistical significance of differences in RMSD, radius of gyration, solvent-accessible surface, number of hydrogen bonds, and secondary structure content between proteins, box types, and the application or not of rotational constraints has been assessed. Furthermore, the differences in the collective modes for each protein between different boxes and the application or not of rotational constraints have been examined. In total 105 simulations were performed, and the results compared using a three-way multivariate analysis of variance (MANOVA) for properties derived from the trajectories and a three-way univariate analysis of variance (ANOVA) for collective modes. It is shown that application of roto-translational constraints does not have a statistically significant effect on the results obtained from the different simulations. However, the choice of simulation box was found to have a small (5-10%), but statistically significant effect on the behavior of two of the three proteins included in the study.

Protein Conformation↗

PubMed2006

Importance of individual side chains for the stability of a protein fold: computational alanine scanning of the insulin monomer.

A new computational approach is proposed to probe the importance of residue side chains for the stability of a protein fold. Computational mutations to estimate protein stability (CMEPS) is based on the notion that the binding free energy corresponding to the complexation of a given side chain, considered as a "pseudo-ligand" of the wild type protein, reflects the importance of this side chain to the thermodynamic stability of the protein. The contribution of a particular side chain to the folding energy is estimated according to the molecular mechanics-generalized born surface area MM-GBSA approach, using a single molecular dynamics simulation trajectory of the wild type protein. CMEPS is a first principles method which does not contain any adjustable parameter that could be fitted to experimental data. The approach is first validated for Barnase and the B1 domain of protein L, for which a correlation coefficient R = 0.73, between experimental and CMEPS calculated DeltaDeltaG values, is found and then applied to the insulin monomer. In the present application, CMEPS replaces each amino acid by an alanine residue. Therefore, most mutations lead to cavities in the protein. From this the change in stability can be correlated with increased cavity volume. For insulin, this correlation is very similar compared with data previously analyzed for T4 lysozyme from an experiment for buried apolar side chains. There, the increased cavity volume has been related to the hydrophobic effect. However, since CMEPS uses the energetics in terms of electrostatic and van der Waals interactions (and not the hydrophobic effect which is difficult to relate to physical interactions), it is possible to study the effect of mutations of polar and solvent accessible side chains. According to CMEPS, residues Leu A16, Tyr A19, Leu B11, Leu B15, and Arg B22 are most important for the stability of the monomeric insulin fold. This is in agreement with experimental data. As a consequence, mutation of these residues may lead to misfolded and inactive insulin analogues.

Alanine↗

PubMed2007

Functional divergence after gene duplication and sequence-structure relationship: a case study of G-protein alpha subunits.

In this article, we use animal G-protein alpha subunit family as an example to illustrate a comprehensive analytical pipeline for detecting different types of functional divergence of protein families, which is phylogeny-dependent, combined with ancestral sequence inference and available protein structure information. In particular, we focus on (i) Type-I functional divergence, or site-specific rate shift, as typically exemplified by amino acid residue highly conserved in a subset of homologous genes but highly variable in a different subset of homologous genes, and (ii) Type-II functional divergence, or the shift of cluster-specific amino acid property, as exemplified by a radical shift of amino acid property between duplicate genes, which is otherwise evolutionally conserved. We utilized the software DIVERGE2 to carry out these analyses. In the case of G-protein alpha subunit gene family, we have predicted amino acid residues that are related to either Type-I or Type-II functional divergence. The inferred ancestral sequences for these sites are helpful to explore the trends of functional divergence. Finally, these predicted residues are mapped to the protein structures to test whether these residues may have 3D structure or solvent accessibility preference.

Amino Acid Sequence↗

PubMed1994

Buried surface analysis of HIV-1 reverse transcriptase p66/p51 heterodimer and its interaction with dsDNA template/primer.

The p66/p51 human immunodeficiency virus type 1 reverse transcriptase is a heterodimer with identical N-terminal amino acid sequences. The enzyme contains two polymerization domains and one RNase H domain, which is located at the C-terminus of the p66 subunit. Both polymerization domains fold into four individual subdomains that are not arranged in a similar fashion, forming an unusually asymmetric dimer. The complexity of the RT p66/p51 heterodimer structure is simplified using solvent-accessibility surface areas to describe the buried surface area of contact among the different subdomains. In addition, the RT/DNA contacts in the recently published RT/DNA/Fab structure [Jacobo-Molina et al., Proc. Natl Acad. Sci. USA, 90, 6320-6324 (1993)] are described using the same approach. Finally, the RT/DNA complex is compared with other dimeric DNA-binding proteins. It was found that the size of the protein and the extent of the dimer interface were not directly related to the extent of contact between the protein and the DNA. Furthermore, RT, the only protein that is not a sequence-specific DNA binding protein in this analysis, had the largest surface of interaction with the nucleic acid.

Binding Sites↗

PubMedDate not supplied

The Poisson-Boltzmann equation for biomolecular electrostatics: a tool for structural biology.

Electrostatics plays a fundamental role in virtually all processes involving biomolecules in solution. The Poisson-Boltzmann equation constitutes one of the most fundamental approaches to treat electrostatic effects in solution. The theoretical basis of the Poisson-Boltzmann equation is reviewed and a wide range of applications is presented, including the computation of the electrostatic potential at the solvent-accessible molecular surface, the computation of encounter rates between molecules in solution, the computation of the free energy of association and its salt dependence, the study of pKa shifts and the combination with classical molecular mechanics and dynamics. Theoretical results may be used for rationalizing or predicting experimental results, or for suggesting working hypotheses. An ever-increasing body of successful applications proves that the Poisson-Boltzmann equation is a useful tool for structural biology and complementary to other established experimental and theoretical methodologies.

Algorithms↗

PubMed2003

Origin of the conformation dependence of protein charge-state distributions in electrospray ionization mass spectrometry.

The influence of tertiary structure on the electrospray ionization mass spectra of proteins is a well known and broadly exploited phenomenon. However, the underlying mechanism is not well understood. This paper discusses the bases and the implications of the two current hypotheses (solvent accessibility and Coulombic repulsions), pointing out the remaining open questions. Evidence reported here supports a third hypothesis, i.e. that intramolecular interactions in folded proteins play a key role in determining the observed charge-state distributions. It is proposed that native protein structures stabilize to a large extent pre-existing charges of the opposite polarity to the net charge of the ion, preventing their neutralization during the electrospray process. Thus, the higher charge states of unfolded conformations, relative to the folded structure, would not derive from a more extensive ionization of the former, but rather from a higher content of neutralizing charges in the latter. This interpretation allows several other problematic observations to be explained, including the different shapes of the spectra of folded and unfolded proteins, the discrepancies between observed and predicted gas-phase reactivity of protein ions and the apparent inconsistency of positive- and negative-ion mode results.

Animals↗

PubMed2003

Role of opposite charges in protein electrospray ionization mass spectrometry.

The conformation dependence of protein spectra recorded by electrospray ionization mass spectrometry (ESI-MS) is an interesting and useful phenomenon, whose origin is still the object of debate. Different mechanisms have been invoked in the attempt to explain the lower charge state of folded versus unfolded protein ions in ESI-MS, such as electrostatic repulsions, solvent accessibility, charge availability, and native-like interactions. In this work we try to subject to direct experimental test the hypothesis that conformation-dependent neutralization of charges with polarity opposite to the net charge of the protein ion could play a critical role in such an effect. We present results of time-of-flight nano-ESI-MS on the peptide angiotensin II, indicating that negative charges of carboxylate groups can contribute to spectra recorded in positive-ion mode when stabilized by favorable electrostatic interactions, which is the central assumption of our hypothesis. Comparison of horse and spermwhale myoglobin (Mb) shows that changing the total number of basic residues within a given three-dimensional structure shifts the charge-state distribution (CSD) of the folded protein in positive-ion mode. This result appears to be in contrast to models in which electrostatic repulsions or availability of charges in the ESI droplets represent the limiting factor for the ionization of folded protein ions in ESI-MS. At the same time, it suggests a role of acidic residues in conformational effects in positive-ion mode. Furthermore, an attempt is made to rationalize those cases in which, in contrast, the main charge state observed in ESI-MS under non-denaturing conditions deviates considerably from the net charge expected on the basis of the amino-acid composition. These cases usually correspond to proteins with quite balanced content in basic and acidic residues, suggesting that this might be a factor influencing their charging behavior in ESI-MS. Experiments on mutants of ribonuclease Sa (RNase Sa) reveal that progressively reducing the excess of acidic residues, replacing them by lysine, causes almost no shift in the spectrum of the folded protein in negative-ion mode. Analogously, variants with an excess of three or five basic residues give similar spectra in positive-ion mode. These results indicate a lower limit to the extent of ionization observable by ESI-MS (6- or 8+ in the case of RNase Sa in water). Below such limit of net charge, changes in the relative amount of ionizable side chains do not affect the qualitative features of the observed CSDs. A progressive loss of signal intensity caused by the mutations in negative-ion mode suggests that low charge states might also be counterselected, even within the m/z range theoretically accessible to the instrument.

Angiotensin II↗

PubMed2005

Novel lipid hydroperoxide-derived hemoglobin histidine adducts as biomarkers of oxidative stress.

Hemoglobin (Hb) adducts have long been used as dosimeters of exposure to xenobiotics and endogenously formed reactive metabolites. In this study, hemoglobin chains were separated from each other and their prosthetic heme groups and reacted with 4-oxo-2-nonenal, a major breakdown product of lipid hydroperoxides. The adducts were characterized by matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-TOF/MS) analysis of the intact proteins and by a combination of liquid chromatography/electrospray ionization/tandem MS (MS/MS) and MALDI-TOF/MS/MS analysis of the tryptic peptides. Covalent modifications were found on both hemoglobin chains. The location was determined to be on H20 of the alpha-hemoglobin chain and on H(63) of the beta-hemoglobin chain. Molecular modeling revealed that these two residues were two most solvent accessible H residues present in intact Hb. The proposed reaction mechanism is based on that described for the reaction of 4-hydroxy-2-nonenal with proteins. Initial nucleophilic Michael addition is followed by hydration of the resulting aldehyde, cyclization, and two sequential dehydration reactions to give stable furan derivatives. This results in the addition of 136 Da from 4-oxo-2-nonenal to give adducts corresponding to (17)VGAH(.) AGEYGAEALER(31) from alpha-hemoglobin and (62)AH(.) GK(65) from beta-hemoglobin. These hemoglobin modifications can potentially serve as biomarkers of lipid hydroperoxide-mediated macromolecule damage and may reflect an indirect measurement of the potential for DNA damage in vivo.

Aldehydes↗

PubMedDate not supplied

Protein-folding kinetics and mechanisms studied by pulse-labeling and mass spectrometry.

The "protein-folding problem" refers to the question of how and why a denatured polypeptide chain can spontaneously fold into a compact and highly ordered conformation. The classical description of this process in terms of reaction pathways has been complemented by models that describe folding as a biased conformational diffusion on a multidimensional energy landscape. The identification and characterization of short-lived intermediates provide important insights into the mechanism of folding. Pulsed hydrogen/deuterium exchange (HDX) methods are among the most powerful tools for studying the properties of kinetic intermediates. Analysis of pulse-labeled proteins by mass spectrometry (MS) provides information that is complementary to that obtained in nuclear magnetic resonance (NMR) studies; NMR data represent an average of entire protein ensembles, whereas MS can detect co-existing protein species. MS-based pulse-labeling experiments can distinguish between folding scenarios that involve parallel pathways, and those where folding is channeled through obligatory intermediates. The proteolytic digestion/MS technique provides spatially resolved information on the HDX pattern of folding intermediates. This method is especially important for proteins that are too large to be studied by NMR. Although traditional pulsed HDX protocols are based on quench-flow techniques, it is also possible to use electrospray (ESI) MS to analyze the reaction mixture on-line and "quasi-instantaneously" after labeling. This approach allows short-lived protein conformations to be studied by their HDX level, their ESI charge-state distribution, and their ligand-binding state. Covalent labeling of free cysteinyl residues provides an alternative approach to pulsed HDX experiments. Another promising development is the use of synchrotron X-rays to induce oxidation at specific sites within a protein for studying their solvent accessibility during folding.

Animals↗

PubMed2004

Prediction of protein-protein interactions based on surface patch comparison.

A method to predict if two proteins interact, based on their three-dimensional structures, is presented. It consists of five steps: (i) the surface of each protein, represented by the solvent accessible atoms, is divided into small patches; (ii) the shape of each patch is described by the atom distributions along its principal axes; (iii) the shape complementarity between two patches is estimated by comparing, through contingency table analysis, their atom distributions along their principal axes; (iv) given protein A, with nA surface patches, and protein B, with nB surface patches, nA x nB shape complementarity values are obtained; and (v) the distribution of the latter allows one to discriminate pairs of interacting and of noninteracting proteins. Only a few seconds are necessary to predict if two proteins interact, with accuracy close to 80%, sensitivity over 70% and specificity close to 50%.

Computational Biology↗