The ff94 force field that is commonly associated with the Amber simulation package is one of the most widely used parameter sets for biomolecular simulation. After a decade of extensive use and testing, limitations in this force field, such as over-stabilization of alpha-helices, were reported by us and other researchers. This led to a number of attempts to improve these parameters, resulting in a variety of "Amber" force fields and significant difficulty in determining which should be used for a particular application. We show that several of these continue to suffer from inadequate balance between different secondary structure elements. In addition, the approach used in most of these studies neglected to account for the existence in Amber of two sets of backbone phi/psi dihedral terms. This led to parameter sets that provide unreasonable conformational preferences for glycine. We report here an effort to improve the phi/psi dihedral terms in the ff99 energy function. Dihedral term parameters are based on fitting the energies of multiple conformations of glycine and alanine tetrapeptides from high level ab initio quantum mechanical calculations. The new parameters for backbone dihedrals replace those in the existing ff99 force field. This parameter set, which we denote ff99SB, achieves a better balance of secondary structure elements as judged by improved distribution of backbone dihedrals for glycine and alanine with respect to PDB survey data. It also accomplishes improved agreement with published experimental data for conformational preferences of short alanine peptides and better accord with experimental NMR relaxation data of test protein systems.

/pdf/comparison-of-multiple-amber-force-fields-and-development-of-2mpeu0hj18.pdf

Comparison of multiple Amber force fields and development of improved protein backbone parameters.

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 e = 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. © 2003 Wiley Periodicals, Inc. J Comput Chem 24: 1999–2012, 2003

/pdf/a-point-charge-force-field-for-molecular-mechanics-4llr9g0zko.pdf

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

Functional characterization of a protein sequence is a common goal in biology, and is usually facilitated by having an accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.

/pdf/comparative-protein-structure-modeling-using-modeller-262v4shee8.pdf

Comparative Protein Structure Modeling Using MODELLER

Functional characterization of a protein sequence is one of the most frequent problems in biology. This task is usually facilitated by accurate three-dimensional (3-D) structure of the studied protein. In the absence of an experimentally determined structure, comparative or homology modeling can sometimes provide a useful 3-D model for a protein that is related to at least one known protein structure. Comparative modeling predicts the 3-D structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described.

/pdf/comparative-protein-structure-modeling-using-modeller-1ye86wsiv7.pdf

Comparative protein structure modeling using Modeller.

Motivation: Protein homology detection and sequence alignment are at the basis of protein structure prediction, function prediction and evolution.

Results: We have generalized the alignment of protein sequences with a profile hidden Markov model (HMM) to the case of pairwise alignment of profile HMMs. We present a method for detecting distant homologous relationships between proteins based on this approach. The method (HHsearch) is benchmarked together with BLAST, PSI-BLAST, HMMER and the profile--profile comparison tools PROF_SIM and COMPASS, in an all-against-all comparison of a database of 3691 protein domains from SCOP 1.63 with pairwise sequence identities below 20%.

Sensitivity: When the predicted secondary structure is included in the HMMs, HHsearch is able to detect between 2.7 and 4.2 times more homologs than PSI-BLAST or HMMER and between 1.44 and 1.9 times more than COMPASS or PROF_SIM for a rate of false positives of 10%. Approximately half of the improvement over the profile--profile comparison methods is attributable to the use of profile HMMs in place of simple profiles.

Alignment quality: Higher sensitivity is mirrored by an increased alignment quality. HHsearch produced 1.2, 1.7 and 3.3 times more good alignments ('balanced' score >0.3) than the next best method (COMPASS), and 1.6, 2.9 and 9.4 times more than PSI-BLAST, at the family, superfamily and fold level, respectively.

Speed: HHsearch scans a query of 200 residues against 3691 domains in 33 s on an AMD64 2GHz PC. This is 10 times faster than PROF_SIM and 17 times faster than COMPASS.

Availability: HHsearch can be downloaded from http://www.protevo.eb.tuebingen.mpg.de/download/ together with up-to-date versions of SCOP and PFAM. A web server is available at http://www.protevo.eb.tuebingen.mpg.de/toolkit/index.php?view=hhpred

Contact: johannes.soeding@tuebingen.mpg.de

/pdf/protein-homology-detection-by-hmm-hmm-comparison-1061gteduj.pdf

Protein homology detection by HMM--HMM comparison

PISCES is a public server for culling sets of protein sequences from the Protein Data Bank (PDB) by sequence identity and structural quality criteria. PISCES can provide lists culled from the entire PDB or from lists of PDB entries or chains provided by the user. The sequence identities are obtained from PSI-BLAST alignments with position-specific substitution matrices derived from the non-redundant protein sequence database. PISCES therefore provides better lists than servers that use BLAST, which is unable to identify many relationships below 40% sequence identity and often overestimates sequence identity by aligning only well-conserved fragments. PDB sequences are updated weekly. PISCES can also cull non-PDB sequences provided by the user as a list of GenBank identifiers, a FASTA format file, or BLAST/PSI-BLAST output.

PISCES: a protein sequence culling server

PISCES is a database server for producing lists of sequences from the Protein Data Bank (PDB) using a number of entry- and chain-specific criteria and mutual sequence identity. Our goal in culling the PDB is to provide the longest list possible of the highest resolution structures that fulfill the sequence identity and structural quality cut-offs. The new PISCES server uses a combination of PSI-BLAST and structure-based alignments to determine sequence identities. Structure alignment produces more complete alignments and therefore more accurate sequence identities than PSI-BLAST. PISCES now allows a user to cull the PDB by-entry in addition to the standard culling by individual chains. In this scenario, a list will contain only entries that do not have a chain that has a sequence identity to any chain in any other entry in the list over the sequence identity cut-off. PISCES also provides fully annotated sequences including gene name and species. The server allows a user to cull an input list of entries or chains, so that other criteria, such as function, can be used. Results from a search on the re-engineered RCSB's site for the PDB can be entered into the PISCES server by a single click, combining the powerful searching abilities of the PDB with PISCES's utilities for sequence culling. The server's data are updated weekly. The server is available at http://dunbrack.fccc.edu/pisces.

/pdf/pisces-recent-improvements-to-a-pdb-sequence-culling-server-3xvllnr2u0.pdf

PISCES: recent improvements to a PDB sequence culling server.

Distributions of the backbone dihedral angles of proteins have been studied for over 40 years. While many statistical analyses have been presented, only a handful of probability densities are publicly available for use in structure validation and structure prediction methods. The available distributions differ in a number of important ways, which determine their usefulness for various purposes. These include: 1) input data size and criteria for structure inclusion (resolution, R-factor, etc.); 2) filtering of suspect conformations and outliers using B-factors or other features; 3) secondary structure of input data (e.g., whether helix and sheet are included; whether beta turns are included); 4) the method used for determining probability densities ranging from simple histograms to modern nonparametric density estimation; and 5) whether they include nearest neighbor effects on the distribution of conformations in different regions of the Ramachandran map. In this work, Ramachandran probability distributions are presented for residues in protein loops from a high-resolution data set with filtering based on calculated electron densities. Distributions for all 20 amino acids (with cis and trans proline treated separately) have been determined, as well as 420 left-neighbor and 420 right-neighbor dependent distributions. The neighbor-independent and neighbor-dependent probability densities have been accurately estimated using Bayesian nonparametric statistical analysis based on the Dirichlet process. In particular, we used hierarchical Dirichlet process priors, which allow sharing of information between densities for a particular residue type and different neighbor residue types. The resulting distributions are tested in a loop modeling benchmark with the program Rosetta, and are shown to improve protein loop conformation prediction significantly. The distributions are available at http://dunbrack.fccc.edu/hdp.

/pdf/neighbor-dependent-ramachandran-probability-distributions-of-1qncbrxe3a.pdf

Neighbor-Dependent Ramachandran Probability Distributions of Amino Acids Developed from a Hierarchical Dirichlet Process Model

High-order harmonics extending to the X-ray region generated in a gas medium by intense lasers offer the potential for providing tabletop broadband light sources but so far are limited by their low conversion efficiency. Here we show that harmonics can be enhanced by one to two orders of magnitude without an increase in the total laser power if the laser's waveform is optimized by synthesizing two- or three-colour fields. The harmonics thus generated are also favourably phase-matched so that radiation is efficiently built up in the gas medium. Our results, combined with the emerging intense high-repetition MHz lasers, promise to increase harmonic yields by several orders to make harmonics feasible in the near future as general bright tabletop light sources, including intense attosecond pulses.

/pdf/waveforms-for-optimal-sub-kev-high-order-harmonics-with-1zqnqvssc0.pdf

Waveforms for optimal sub-keV high-order harmonics with synthesized two- or three-colour laser fields

A common technical difficulty in device-free localization and tracking (DFLT) with a wireless sensor network is that the change of the received signal strength (RSS) of the link often becomes more unpredictable due to the multipath interferences. This challenge can lead to unsatisfactory or even unstable DFLT performance. This work focuses on developing a new RSS model, called Exponential-Rayleigh (ER) model, for addressing this challenge. Based on data from our extensive experiments, we first develop the ER model of the received signal strength. This model consists of two parts: the large-scale exponential attenuation part and the small-scale Rayleigh enhancement part. The new consideration on using the Rayleigh model is to depict the target-induced multipath components. We then explore the use of the ER model with a particle filter in the context of multi-target localization and tracking. Finally, we experimentally demonstrate that our ER model outperforms the existing models. The experimental results highlight the advantages of using the Rayleigh model in mitigating the multipath interferences thus improving the DFLT performance.

Guoli Wang

Papers

PISCES: a protein sequence culling server

PISCES: recent improvements to a PDB sequence culling server.

Neighbor-Dependent Ramachandran Probability Distributions of Amino Acids Developed from a Hierarchical Dirichlet Process Model

Waveforms for optimal sub-keV high-order harmonics with synthesized two- or three-colour laser fields

An Exponential-Rayleigh Model for RSS-Based Device-Free Localization and Tracking