Biomedical subjects

Ray Luo

Publications and source records attributed to Ray Luo.

12 recordsLinked to original sources

PubMed2006

How well does Poisson-Boltzmann implicit solvent agree with explicit solvent? A quantitative analysis.

We have quantitatively studied the performance of a finite-difference Poisson-Boltzmann implicit solvent with respect to the TIP3P explicit solvent in a range of systems of biochemical interest. An overall agreement was found between the tested implicit and explicit solvents for hydrogen-bonding/salt-bridging dimers and peptide monomers and dimers of different conformations and different lengths. These comparative analyses also indicate a good transferability of empirically optimized parameters for the implicit solvent from small training molecules to large testing peptides. However, deviations between the two tested solvents are also apparent. Specifically, a consistent deviation was observed when hydrogen-bonding or salt-bridging dimers are within 4-6 A. The deviation reaches a maximum at about 5.5 A, the so-called water-bridging distance. The tested implicit solvent, even with optimized parameters, cannot capture the subtle fluctuation in the distance-dependent reaction field energy profiles, although smoothed profiles can still be obtained and are in overall agreement with those in the explicit solvent. Interestingly, the same mechanism underlining the above discrepancy is also responsible for the larger deviations of certain peptide conformations, such as parallel beta-strand dimers. It is likely that the observed discrepancy may cause improper conformational distributions in simulations with the implicit solvent when hydrogen-bonding or salt-bridging interactions are crucial, such as secondary structure populations in proteins. Validation of the implicit solvent with optimized parameters in dynamics simulations will be the next step to study the influences of the observed discrepancy at biological conditions.

Alanine↗

PubMed2006

New-generation amber united-atom force field.

We have developed a new-generation Amber united-atom force field for simulations involving highly demanding conformational sampling such as protein folding and protein-protein binding. In the new united-atom force field, all hydrogens on aliphatic carbons in all amino acids are united with carbons except those on Calpha. Our choice of explicit representation of all protein backbone atoms aims at minimizing perturbation to protein backbone conformational distributions and to simplify development of backbone torsion terms. Tests with dipeptides and solvated proteins show that our goal is achieved quite successfully. The new united-atom force field uses the same new RESP charging scheme based on B3LYP/cc-pVTZ//HF/6-31g** quantum mechanical calculations in the PCM continuum solvent as that in the Duan et al. force field. van der Waals parameters are empirically refitted starting from published values with respect to experimental solvation free energies of amino acid side-chain analogues. The suitability of mixing new point charges and van der Waals parameters with existing Amber covalent terms is tested on alanine dipeptide and is found to be reasonable. Parameters for all new torsion terms are refitted based on the new point charges and the van der Waals parameters. Molecular dynamics simulations of three small globular proteins in the explicit TIP3P solvent are performed to test the overall stability and accuracy of the new united-atom force field. Good agreements between the united-atom force field and the Duan et al. all-atom force field for both backbone and side-chain conformations are observed. In addition, the per-step efficiency of the new united-atom force field is demonstrated for simulations in the implicit generalized Born solvent. A speedup around two is observed over the Duan et al. all-atom force field for the three tested small proteins. Finally, the efficiency gain of the new united-atom force field in conformational sampling is further demonstrated with a well-known toy protein folding system, an 18 residue polyalanine in distance-dependent dielectric. The new united-atom force field is at least a factor of 200 more efficient than the Duan et al. all-atom force field for ab initio folding of the tested peptide.

Models, Molecular↗

PubMed2006

Is Poisson-Boltzmann theory insufficient for protein folding simulations?

The Poisson-Boltzmann theory has been widely used in the studies of energetics and conformations of biological macromolecules. Recently, introduction of the efficient generalized Born approximation has greatly extended its applicability to areas such as protein folding simulations where highly efficient computation is crucial. However, limitations have been found in the folding simulations of a well-studied beta hairpin with several generalized Born implementations and different force fields. These studies have raised the question whether the underlining Poisson-Boltzmann theory, on which the generalized Born model is calibrated, is adequate in the treatment of polar interactions for the challenging protein folding simulations. To address the question whether the Poisson-Boltzmann theory in the current formalism might be insufficient, we directly tested our efficient numerical Poisson-Boltzmann implementation in the beta-hairpin folding simulation. Good agreement between simulation and experiment was found for the beta-hairpin equilibrium structures when the numerical Poisson-Boltzmann solvent and a recently improved generalized Born solvent were used. In addition simulated thermodynamic properties also agree well with experiment in both solvents. Finally, an overall agreement on the beta-hairpin folding mechanism was found between the current and previous studies. Thus, our simulations indicate that previously observed limitations are most likely due to imperfect calibration in previous generalized Born models but not due to the limitation of the Poisson-Boltzmann theory.

Amines↗

PubMed2006

Force field influences in beta-hairpin folding simulations.

All-atom force fields are now routinely used for more detailed understanding of protein folding mechanisms. However, it has been pointed out that use of all-atom force fields does not guarantee more accurate representations of proteins; in fact, sometimes it even leads to biased structural distributions. Indeed, several issues remain to be solved in force field developments, such as accurate treatment of implicit solvation for efficient conformational sampling and proper treatment of backbone interactions for secondary structure propensities. In this study, we first investigate the quality of several recently improved backbone interaction schemes in AMBER for folding simulations of a beta-hairpin peptide, and further study their influences on the peptide's folding mechanism. Due to the significant number of simulations needed for a thorough analysis of tested force fields, the implicit Poisson-Boltzmann solvent was used in all simulations. The chosen implicit solvent was found to be reasonable for studies of secondary structures based on a set of simulations of both alpha-helical and beta-hairpin peptides with the TIP3P explicit solvent as benchmark. Replica exchange molecular dynamics was also utilized for further efficient conformational sampling. Among the tested AMBER force fields, ff03 and a revised ff99 force field were found to produce structural and thermodynamic data in comparably good agreement with the experiment. However, detailed folding pathways, such as the order of backbone hydrogen bond zipping and the existence of intermediate states, are different between the two force fields, leading to force field-dependent folding mechanisms.

Computer Simulation↗

PubMed2005

Overcoming entropic barrier with coupled sampling at dual resolutions.

An enhanced sampling method is proposed for ab initio protein folding simulations. The new method couples a high-resolution model for accuracy and a low-resolution model for efficiency. It aims to overcome the entropic barrier found in the exponentially large protein conformational space when a high-resolution model, such as an all-atom molecular mechanics force field, is used. The proposed method is designed to satisfy the detailed balance condition so that the Boltzmann distribution can be generated in all sampling trajectories in both high and low resolutions. The method was tested on model analytical energy functions and ab initio folding simulations of a beta-hairpin peptide. It was found to be more efficient than replica-exchange method that is used as its building block. Analysis with the analytical energy functions shows that the number of energy calculations required to find global minima and to converge mean potential energies is much fewer with the new method. Ergodic measure shows that the new method explores the conformational space more rapidly. We also studied imperfect low-resolution energy models and found that the introduction of errors in low-resolution models does decrease its sampling efficiency. However, a reasonable increase in efficiency is still observed when the global minima of the low-resolution models are in the vicinity of the global minimum basin of the high-resolution model. Finally, our ab initio folding simulation of the tested peptide shows that the new method is able to fold the peptide in a very short simulation time. The structural distribution generated by the new method at the equilibrium portion of the trajectory resembles that in the equilibrium simulation starting from the crystal structure.

Algorithms↗

PubMed2005

The Amber biomolecular simulation programs.

We describe the development, current features, and some directions for future development of the Amber package of computer programs. This package evolved from a program that was constructed in the late 1970s to do Assisted Model Building with Energy Refinement, and now contains a group of programs embodying a number of powerful tools of modern computational chemistry, focused on molecular dynamics and free energy calculations of proteins, nucleic acids, and carbohydrates.

Algorithms↗

PubMed2004

Physical scoring function based on AMBER force field and Poisson-Boltzmann implicit solvent for protein structure prediction.

A well-behaved physics-based all-atom scoring function for protein structure prediction is analyzed with several widely used all-atom decoy sets. The scoring function, termed AMBER/Poisson-Boltzmann (PB), is based on a refined AMBER force field for intramolecular interactions and an efficient PB model for solvation interactions. Testing on the chosen decoy sets shows that the scoring function, which is designed to consider detailed chemical environments, is able to consistently discriminate all 62 native crystal structures after considering the heteroatom groups, disulfide bonds, and crystal packing effects that are not included in the decoy structures. When NMR structures are considered in the testing, the scoring function is able to discriminate 8 out of 10 targets. In the more challenging test of selecting near-native structures, the scoring function also performs very well: for the majority of the targets studied, the scoring function is able to select decoys that are close to the corresponding native structures as evaluated by ranking numbers and backbone Calpha root mean square deviations. Various important components of the scoring function are also studied to understand their discriminative contributions toward the rankings of native and near-native structures. It is found that neither the nonpolar solvation energy as modeled by the surface area model nor a higher protein dielectric constant improves its discriminative power. The terms remaining to be improved are related to 1-4 interactions. The most troublesome term is found to be the large and highly fluctuating 1-4 electrostatics term, not the dihedral-angle term. These data support ongoing efforts in the community to develop protein structure prediction methods with physics-based potentials that are competitive with knowledge-based potentials.

Algorithms↗

PubMed2004

Interplay of secondary structures and side-chain contacts in the denatured state of BBA1.

The denatured state of a miniprotein BBA1 is studied under the native condition with the AMBER/Poisson-Boltzmann energy model and with the self-guided enhanced sampling technique. Forty independent trajectories are collected to sample the highly diversified denatured structures. Our simulation data show that the denatured BBA1 contains high percentage of native helix and native turn, but low percentage of native hairpin. Conditional population analysis indicates that the native helix formation and the native hairpin formation are not cooperative in the denatured state. Side-chain analysis shows that the native hydrophobic contacts are more preferred than the non-native hydrophobic contacts in the denatured BBA1. In contrast, the salt-bridge contacts are more or less nonspecific even if their populations are higher than those of hydrophobic contacts. Analysis of the trajectories shows that the native helix mostly initiates near the N terminus and propagates to the C terminus, and mostly forms from 3(10)-helix/turn to alpha helix. The same analysis shows that the native turn is important but not necessary in its formation in the denatured BBA1. In addition, the formations of the two strands in the native hairpin are rather asymmetric, demonstrating the likely influence of the protein environment. Energetic analysis shows that the native helix formation is largely driven by electrostatic interactions in denatured BBA1. Further, the native helix formation is associated with the breakup of non-native salt-bridge contacts and the accumulation of native salt-bridge contacts. However, the native hydrophobic contacts only show a small increase upon the native helix formation while the non-native hydrophobic contacts stay essentially the same, different from the evolution of hydrophobic contacts observed in an isolated helix folding.

Biophysical Phenomena↗

PubMed2004

Enhanced ab initio protein folding simulations in Poisson-Boltzmann molecular dynamics with self-guiding forces.

We have investigated the sampling efficiency in molecular dynamics with the PB implicit solvent when self-guiding forces are added. Compared with a high-temperature dynamics simulation, the use of self-guiding forces in room-temperature dynamics is found to be rather efficient as measured by potential energy fluctuation, gyration radius fluctuation, backbone RMSD fluctuation, number of unique clusters, and distribution of low RMSD structures over simulation time. Based on the enhanced sampling method, we have performed ab initio folding simulations of two small proteins, betabetaalpha1 and villin headpiece. The preliminary data for the folding simulations is presented. It is found that betabetaalpha1 folding proceeds by initiation of the turn and the helix. The hydrophobic collapse seems to be lagging behind or at most concurrent with the formation of the helix. The hairpin stability is weaker than the helix in our simulations. Its role in the early folding events seems to be less important than the more stable helix. In contrast, villin headpiece folding proceeds first by hydrophobic collapse. The formation of helices is later than the collapse phase, different from the betabetaalpha1 folding.

Computer Simulation↗

PubMed2003

A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations.

Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed.

Algorithms↗

PubMed2002

Accelerated Poisson-Boltzmann calculations for static and dynamic systems.

We report here an efficient implementation of the finite difference Poisson-Boltzmann solvent model based on the Modified Incomplete Cholsky Conjugate Gradient algorithm, which gives rather impressive performance for both static and dynamic systems. This is achieved by implementing the algorithm with Eisenstat's two optimizations, utilizing the electrostatic update in simulations, and applying prudent approximations, including: relaxing the convergence criterion, not updating Poisson-Boltzmann-related forces every step, and using electrostatic focusing. It is also possible to markedly accelerate the supporting routines that are used to set up the calculations and to obtain energies and forces. The resulting finite difference Poisson-Boltzmann method delivers efficiency comparable to the distance-dependent dielectric model for a system tested, HIV Protease, making it a strong candidate for solution-phase molecular dynamics simulations. Further, the finite difference method includes all intrasolute electrostatic interactions, whereas the distance dependent dielectric calculations use a 15-A cutoff. The speed of our numerical finite difference method is comparable to that of the pair-wise Generalized Born approximation to the Poisson-Boltzmann method.

Algorithms↗

PubMedDate not supplied

Functional census of mutation sequence spaces: the example of p53 cancer rescue mutants.

Many biomedical problems relate to mutant functional properties across a sequence space of interest, e.g., flu, cancer, and HIV. Detailed knowledge of mutant properties and function improves medical treatment and prevention. A functional census of p53 cancer rescue mutants would aid the search for cancer treatments from p53 mutant rescue. We devised a general methodology for conducting a functional census of a mutation sequence space by choosing informative mutants early. The methodology was tested in a double-blind predictive test on the functional rescue property of 71 novel putative p53 cancer rescue mutants iteratively predicted in sets of three (24 iterations). The first double-blind 15-point moving accuracy was 47 percent and the last was 86 percent; r = 0.01 before an epiphanic 16th iteration and r = 0.92 afterward. Useful mutants were chosen early (overall r = 0.80). Code and data are freely available (http://www.igb.uci.edu/research/research.html, corresponding authors: R.H.L. for computation and R.K.B. for biology).

Artificial Intelligence↗