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Molecular modelling encompasses all methods, theoretical and computational, used to model or mimic the behaviour of molecules. The methods are used in the fields of computational chemistry, drug design, computational biology and materials science to study molecular systems ranging from small chemical systems to large biological molecules and material assemblies. The simplest calculations can be performed by hand, but inevitably computers are required to perform molecular modelling of any reasonably sized system. The common feature of molecular modelling methods is the atomistic level description of the molecular systems. This may include treating atoms as the smallest individual unit, or explicitly modelling electrons of each atom.
CASTEP is a shared-source academic and commercial software package which uses density functional theory with a plane wave basis set to calculate the electronic properties of crystalline solids, surfaces, molecules, liquids and amorphous materials from first principles. CASTEP permits geometry optimisation and finite temperature molecular dynamics with implicit symmetry and geometry constraints, as well as calculation of a wide variety of derived properties of the electronic configuration. Although CASTEP was originally a serial, Fortran 77-based program, it was completely redesigned and rewritten from 1999-2001 using Fortran 95 and MPI for use on parallel computers by researchers at the Universities of York, Durham, St. Andrews, Cambridge and Rutherford Labs.
In the context of molecular modeling, a force field refers to the functional form and parameter sets used to calculate the potential energy of a system of atoms or coarse-grained particles in molecular mechanics and molecular dynamics simulations. The parameters of the energy functions may be derived from experiments in physics or chemistry, calculations in quantum mechanics, or both.
Nuclear magnetic resonance spectroscopy of proteins is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, and Angela Gronenborn at the NIH, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.
ICM stands for Internal Coordinate Mechanics and was first designed and built to predict low-energy conformations of molecules by sampling the space of internal coordinates defining molecular geometry. In ICM each molecule is constructed as a tree from an entry atom where each next atom is built iteratively from the preceding three atoms via three internal variables. The rings kept rigid or imposed via additional restraints.
X-PLOR is a computer software package for computational structural biology originally developed by Axel T. Brunger at Yale University. It was first published in 1987 as an offshoot of CHARMM - a similar program that ran on supercomputers made by Cray Inc. It is used in the fields of X-ray crystallography and nuclear magnetic resonance spectroscopy of proteins (NMR) analysis.
Xplor-NIH is a highly sophisticated and flexible biomolecular structure determination program which includes an interface to the legacy X-PLOR program. The main developers are Charles Schwieters and Marius Clore of the National Institutes of Health. Xplor-NIH is based on a C++ framework with an extensive Python interface enabling very powerful and easy scripting of complex structure determination and refinement protocols. Restraints derived from all current solution and many solid state nuclear magnetic resonance (NMR) and X-ray scattering experiments can be accommodated during structure calculations. Extensive facilities are also available for many types of ensemble calculations where the experimental data cannot be accounted for by a unique structure. Many of the structure calculation protocols involve the use of simulated annealing designed to overcome local minima on the path of the global minimum region of the target function. These calculations can be carried out using any combination of Cartesian, torsion angle and rigid body dynamics and minimization. Currently Xplor-NIH is the most versatile, comprehensive and widely used structure determination/refinement package in NMR structure determination.
Tinker, stylized as TINKER, is a computer software application for molecular dynamics simulation with a complete and general package for molecular mechanics and molecular dynamics, with some special features for biopolymers. The core of the package is a modular set of callable routines which allow manipulating coordinates and evaluating potential energy and derivatives via straightforward means.
Carbohydrate NMR Spectroscopy is the application of nuclear magnetic resonance (NMR) spectroscopy to structural and conformational analysis of carbohydrates. This method allows the scientists to elucidate structure of monosaccharides, oligosaccharides, polysaccharides, glycoconjugates and other carbohydrate derivatives from synthetic and natural sources. Among structural properties that could be determined by NMR are primary structure, saccharide conformation, stoichiometry of substituents, and ratio of individual saccharides in a mixture. Modern high field NMR instruments used for carbohydrate samples, typically 500 MHz or higher, are able to run a suite of 1D, 2D, and 3D experiments to determine a structure of carbohydrate compounds.
Structure-Based Assignment (SBA) is a technique to accelerate the resonance assignment which is a key bottleneck of NMR structural biology. A homologous (similar) protein is used as a template to the target protein in SBA. This template protein provides prior structural information about the target protein and leads to faster resonance assignment. By analogy, in X-ray Crystallography, the molecular replacement technique allows solution of the crystallographic phase problem when a homologous structural model is known, thereby facilitating rapid structure determination. Some of the SBA algorithms are CAP which is an RNA assignment algorithm which performs an exhaustive search over all permutations, MARS which is a program for robust automatic backbone assignment and Nuclear Vector Replacement (NVR) which is a molecular replacement like approach for SBA of resonances and sparse Nuclear Overhauser Effect (NOE)'s.
Random coil index (RCI) predicts protein flexibility by calculating an inverse weighted average of backbone secondary chemical shifts and predicting values of model-free order parameters as well as per-residue RMSD of NMR and molecular dynamics ensembles from this parameter.
WeNMR is a worldwide e-Infrastructure for NMR spectroscopy and Structural biology. It is the largest Virtual Organization in the Life sciences and is supported by EGI.
CS-ROSETTA is a framework for structure calculation of biological macromolecules on the basis of conformational information from NMR, which is built on top of the biomolecular modeling and design software called ROSETTA. The name CS-ROSETTA for this branch of ROSETTA stems from its origin in combining NMR chemical shift (CS) data with ROSETTA structure prediction protocols. The software package was later extended to include additional NMR conformational parameters, such as Residual Dipolar Couplings (RDC), NOE distance restraints, pseudocontact chemical shifts (PCS) and restraints derived from homologous proteins. This software can be used together with other molecular modeling protocols, such as docking to model protein oligomers. In addition, CS-ROSETTA can be combined with chemical shift resonance assignment algorithms to create a fully automated NMR structure determination pipeline. The CS-ROSETTA software is freely available for academic use and can be licensed for commercial use. A software manual and tutorials are provided on the supporting website https://csrosetta.chemistry.ucsc.edu/.
GeNMR method is the first fully automated template-based method of protein structure determination that utilizes both NMR chemical shifts and NOE -based distance restraints.
CS23D is a web server to generate 3D structural models from NMR chemical shifts. CS23D combines maximal fragment assembly with chemical shift threading, de novo structure generation, chemical shift-based torsion angle prediction, and chemical shift refinement. CS23D makes use of RefDB and ShiftX.
The chemical shift index or CSI is a widely employed technique in protein nuclear magnetic resonance spectroscopy that can be used to display and identify the location as well as the type of protein secondary structure found in proteins using only backbone chemical shift data The technique was invented by Dr. David Wishart in 1992 for analyzing 1Hα chemical shifts and then later extended by him in 1994 to incorporate 13C backbone shifts. The original CSI method makes use of the fact that 1Hα chemical shifts of amino acid residues in helices tends to be shifted upfield relative to their random coil values and downfield in beta strands. Similar kinds of upfield/downfiled trends are also detectable in backbone 13C chemical shifts.
Protein chemical shift prediction is a branch of biomolecular nuclear magnetic resonance spectroscopy that aims to accurately calculate protein chemical shifts from protein coordinates. Protein chemical shift prediction was first attempted in the late 1960s using semi-empirical methods applied to protein structures solved by X-ray crystallography. Since that time protein chemical shift prediction has evolved to employ much more sophisticated approaches including quantum mechanics, machine learning and empirically derived chemical shift hypersurfaces. The most recently developed methods exhibit remarkable precision and accuracy.
PREDITOR is a freely available web-server for the prediction of protein torsion angles from chemical shifts. For many years it has been known that protein chemical shifts are sensitive to protein secondary structure, which in turn, is sensitive to backbone torsion angles. torsion angles are internal coordinates that can be used to describe the conformation of a polypeptide chain. They can also be used as constraints to help determine or refine protein structures via NMR spectroscopy. In proteins there are four major torsion angles of interest: phi, psi, omega and chi-1. Traditionally protein NMR spectroscopists have used vicinal J-coupling information and the Karplus relation to determine approximate backbone torsion angle constraints for phi and chi-1 angles. However, several studies in the early 1990s pointed out the strong relationship between 1H and 13C chemical shifts and torsion angles, especially with backbone phi and psi angles. Later a number of other papers pointed out additional chemical shift relationships with chi-1 and even omega angles. PREDITOR was designed to exploit these experimental observations and to help NMR spectroscopists easily predict protein torsion angles from chemical shift assignments. Specifically, PREDITOR accepts protein sequence and/or chemical shift data as input and generates torsion angle predictions for phi, psi, omega and chi-1 angles. The algorithm that PREDITOR uses combines sequence alignment, chemical shift alignment and a number of related chemical shift analysis techniques to predict torsion angles. PREDITOR is unusually fast and exhibits a very high level of accuracy. In a series of tests 88% of PREDITOR’s phi/psi predictions were within 30 degrees of the correct values, 84% of chi-1 predictions were correct and 99.97% of PREDITOR’s predicted omega angles were correct. PREDITOR also estimates the torsion angle errors so that its torsion angle constraints can be used with standard protein structure refinement software, such as CYANA, CNS, XPLOR and AMBER. PREDITOR also supports automated protein chemical shift re-referencing and the prediction of proline cis/trans states. PREDITOR is not the only torsion angle prediction software available. Several other computer programs including TALOS, TALOS+ and DANGLE have also been developed to predict backbone torsion angles from protein chemical shifts. These stand-alone programs exhibit similar prediction performance to PREDITOR but are substantially slower.
Volume, Area, Dihedral Angle Reporter (VADAR) is a freely available protein structure validation web server that was developed as a collaboration between Dr. Brian Sykes and Dr. David Wishart at the University of Alberta. VADAR consists of >15 different algorithms and programs for assessing and validating peptide and protein structures from their PDB coordinate data. VADAR is capable of determining secondary structure, identifying and classifying six different types of beta turns, determining and calculating the strength of C=O -- N-H hydrogen bonds, calculating residue-specific accessible surface areas (ASA), calculating residue volumes, determining backbone and side chain torsion angles, assessing local structure quality, evaluating global structure quality and identifying residue “outliers”. The results have been validated through extensive comparison to published data and careful visual inspection. VADAR produces both text and graphical output with most of the quantitative data presented in easily viewed tables. In particular, VADAR’s output is presented in a vertical, tabular format with most of the sequence data, residue numbering and any other calculated property or feature presented from top to bottom, rather than from left to right.
G. Marius Clore FRSC is a British-born, American molecular biophysicist and structural biologist. He was born in London, U.K. and is a dual US/U.K. Citizen. He is a member of the United States National Academy of Sciences, a NIH Distinguished Investigator, and the Chief of the Protein NMR Spectroscopy Section in the Laboratory of Chemical Physics of the National Institute of Diabetes and Digestive and Kidney Diseases at the U.S. National Institutes of Health. He is known for his foundational work in three-dimensional protein and nucleic acid structure determination by biomolecular NMR spectroscopy, for advancing experimental approaches to the study of large macromolecules and their complexes by NMR, and for developing NMR-based methods to study rare conformational states in protein-nucleic acid and protein-protein recognition.