Applying an Empirical Hydropathic Forcefield in Refinement May Improve Low-Resolution Protein X-Ray Crystal Structures (original) (raw)
Related papers
Journal of Computer-Aided Molecular Design, 2018
In this perspective, we review the theory and methodology of the derivation of force fields (FFs), and their validity, for molecular simulations, from their inception in the second half of the twentieth century to the improved representations at the end of the century. We examine the representations of the physics embodied in various force fields, their accuracy and deficiencies. The early days in the 1950s and 60s saw FFs first introduced to analyze vibrational spectra. The advent of computers was soon followed by the first molecular mechanics machine calculations. From the very first papers it was recognized that the accuracy with which the FFs represented the physics was critical if meaningful calculated structural and thermodynamic properties were to be achieved. We discuss the rigorous methodology formulated by Lifson, and later Allinger to derive molecular FFs, not only obtain optimal parameters but also uncover deficiencies in the representation of the physics and improve the functional form to account for this physics. In this context, the known coupling between valence coordinates and the importance of coupling terms to describe the physics of this coupling is evaluated. Early simplified, truncated FFs introduced to allow simulations of macromolecular systems are reviewed and their subsequent improvement assessed. We examine in some depth: the basis of the reformulation of the H-bond to its current description; the early introduction of QM in FF development methodology to calculate partial charges and rotational barriers; the powerful and abundant information provided by crystal structure and energetic observables to derive and test all aspects of a FF including both nonbond and intramolecular functional forms; the combined use of QM, along with crystallography and lattice energy calculations to derive rotational barriers about ɸ and ψ; the development and results of methodologies to derive "QM FFs" by sampling the QM energy surface, either by calculating energies at hundreds of configurations, or by describing the energy surface by energies, first and second derivatives sampled over the surface; and the use of the latter to probe the validity of the representations of the physics, reveal flaws and assess improved functional forms. Research demonstrating significant effects of the flaws in the use of the improper torsion angle to represent out of plane deformations, and the standard Lorentz-Berthelot combining rules for nonbonded interactions, and the more accurate descriptions presented are also reviewed. Finally, we discuss the thorough studies involved in deriving the 2nd generation all-atom versions of the CHARMm, AMBER and OPLS FFs, and how the extensive set of observables used in these studies allowed, in the spirit of Lifson, a characterization of both the abilities, but more importantly the deficiencies in the diagonal 12-6-1 FFs used. The significant contribution made by the extensive set of observables compiled in these papers as a basis to test improved forms is noted. In the following paper, we discuss the progress in improving the FFs and representations of the physics that have been investigated in the years following the research described above.
2014
for all their help and support. Dr. Safo's group especially Christina Camara for teaching me many experimental procedures. Dr. Hardik Parikh and all Dr. Kellogg's group for their help and insights. My wife Esraa, who went through a lot with me and who always kept encouraging me to go on. She transformed my life for the better. I would also like to thank her family for all of their support. My Son Ibrahim whom I had to borrow a lot of his father-son time to finish this work. My father, mother and my sisters as I would not be who I am now if it was not for them. My Friends Dr. Osama Shoair, my life in Richmond would have been harder if it were not for him, Mr. Erik Langer and Mr. Osama El-Mahdy, whom have always been there for me. I value their friendship.
An improved hydrogen bond potential: impact on medium resolution protein structures
Protein science : a publication of the Protein Society, 2002
A new semi-empirical force field has been developed to describe hydrogen-bonding interactions with a directional component. The hydrogen bond potential supports two alternative target angles, motivated by the observation that carbonyl hydrogen bond acceptor angles have a bimodal distribution. It has been implemented as a module for a macromolecular refinement package to be combined with other force field terms in the stereochemically restrained refinement of macromolecules. The parameters for the hydrogen bond potential were optimized to best fit crystallographic data from a number of protein structures. Refinement of medium-resolution structures with this additional restraint leads to improved structure, reducing both the free R-factor and over-fitting. However, the improvement is seen only when stringent hydrogen bond selection criteria are used. These findings highlight common misconceptions about hydrogen bonding in proteins, and provide explanations for why the explicit hydroge...
Molecular Mechanics Force Fields and their Applications in Drug Design
2009
The molecular structures, properties and energies of a molecule are better understood through the use of the "mechanical" molecular model. This model involves the development of a simple molecular mechanics energy equation representing the sum of various energy interaction terms comprised of bonds, angles, torsions of bonded, as well as, nonbonded atoms. Referred to as "force fields", the model serves as a simple "descriptor" for vibrations in molecules. The concept of force fields is now widely employed as one of the simplest tools in molecular modeling.
Hydrophobic-Hydrophilic Forces and their Effects on Protein Structural Similarity
Hydrophobic-Hydrophilic interactions have a strong impact on the three-dimensional structure a protein will adopt. Because structure, not amino acid sequence order, carry out certain functions it is important to understand how these forces affect the protein folding process. In recent years, a lot of focus has been dedicated towards ab initio protein folding prediction, which tries to predict a proteins native conformation from its sequence alone. To aid this type of prediction sub-conformations from already known proteins are used to limit the free energy conformational search space. In this paper we looked into the subconformations' hydrophobic-hydrophilic nature by incorporating a HP model and proposed a way of evaluating how these type of forces affect the protein folding process. By doing this, we can gain insight into how hydrophobic-hydrophilic interactions affect protein structural similarity, and thus aid us in picking more suitable sub-conformations based off their HP ...
Further Optimization and Validation of the Classical Drude Polarizable Protein Force Field
The CHARMM Drude-2013 polarizable force field (FF) was developed to include the explicit treatment of induced electronic polarizability, resulting in a more accurate description of the electrostatic interactions in molecular dynamics (MD) simulations. While the Drude-2013 protein FF has shown success in improving the folding properties of α-helical peptides and to reproduce experimental observables in simulations up to 1 μs, some limitations were noted regarding the stability of β-sheet structures in simulations longer than 100 ns as well as larger deviations from crystal structures in simulations of a number of proteins compared to the additive CHARMM36 protein FF. The origin of the instability has been identified and appears to be primarily due to overestimated atomic polarizabilities and induced dipole-dipole interactions on the Cβ, Cγ and Cδ side chain atoms. To resolve this and other issues, a number of aspects of the model were revisited, resulting in Drude-2019 protein FF. Backbone parameters were optimized targeting the conformational properties of the (Ala) 5 peptide in solution along with gas phase properties of the alanine dipeptide. Dipeptides that contain N-acetylated and N'-methylamidated termini, excluding Gly, Pro and Ala, were used as models to optimize the atomic polarizabilities and Thole screening factors on selected Cβ, Cγ and Cδ carbons by targeting quantum mechanical (QM) dipole moments and molecular polarizabilities. In addition, to obtain better conformational properties, side chain χ1 and χ2 dihedral parameters were optimized targeting QM data for the respective side chain dipeptide conformations as well as PDB survey data based on the χ1, χ2 sampling from Hamiltonian replica-exchange MD simulations of (Ala) 4-X-(Ala) 4 in solution, where X is the amino acid of interest. Further improvements include optimizing nonbonded interactions between charged residues to reproduce QM interactions energies of the charged-protein model compounds ‡
Better force fields start with better data: A data set of cation dipeptide interactions
Scientific Data, 2022
We present a data set from a first-principles study of amino-methylated and acetylated (capped) dipeptides of the 20 proteinogenic amino acids-including alternative possible side chain protonation states and their interactions with selected divalent cations (Ca 2+ , Mg 2+ and Ba 2+). The data covers 21,909 stationary points on the respective potential-energy surfaces in a wide relative energy range of up to 4 eV (390 kJ/mol). Relevant properties of interest, like partial charges, were derived for the conformers. The motivation was to provide a solid data basis for force field parameterization and further applications like machine learning or benchmarking. In particular the process of creating all this data on the same first-principles footing, i.e. density-functional theory calculations employing the generalized gradient approximation with a van der Waals correction, makes this data suitable for first principles data-driven force field development. To make the data accessible across domain borders and to machines, we formalized the metadata in an ontology.
Journal of Chemical Theory and Computation, 2015
Modeling of macromolecular structures and interactions represents an important challenge for computational biology, involving different time and length scales. However, this task can be facilitated through the use of coarse-grained (CG) models, which reduce the number of degrees of freedom and allow efficient exploration of complex conformational spaces. This article presents a new CG protein model named SIRAH, developed to work with explicit solvent and to capture sequence, temperature, and ionic strength effects in a topologically unbiased manner. SIRAH is implemented in GROMACS, and interactions are calculated using a standard pairwise Hamiltonian for classical molecular dynamics simulations. We present a set of simulations that test the capability of SIRAH to produce a qualitatively correct solvation on different amino acids, hydrophilic/ hydrophobic interactions, and long-range electrostatic recognition leading to spontaneous association of unstructured peptides and stable structures of single polypeptides and protein−protein complexes. a N indicates the number of residues. Values reported correspond to the average calculated over the last 100 ns of each μs. Parentheses and square brackets indicate standard deviations and values calculated from the experimental structure, respectively.
Journal of Physical Chemistry B, 2010
We use classical molecular dynamics and sixteen combinations of force fields and water models to simulate a protein crystal observed by room-temperature X-ray diffraction. The high resolution of the diffraction data (0.96Å) and the simplicity of the crystallization solution (nearly pure water) makes it possible to attribute any inconsistencies between the crystal structure and our simulations to artifacts of the models rather than inadequate representation of the crystal environment or uncertainty in the experiment. All simulations were extended for 100ns of production dynamics, permitting some long-timescale artifacts of each model to emerge. The most noticeable effect of these artifacts is a model-dependent drift in the unit cell dimensions, which can become as large as 5% in certain force fields; the underlying cause is the replacement of native crystallographic contacts with non-native ones, which can occur with heterogeneity (loss of crystallographic symmetry) in simulations with some force fields. We find that the AMBER FF99SB force field maintains a lattice structure nearest that seen in the X-ray data, and produces the most realistic atomic fluctuations (by comparison to crystallographic B-factors) of all the models tested. We find that the choice of water model has a minor effect in comparison to the choice of protein model. We also identify a number of artifacts that occur throughout all of the simulations: excessive formation of hydrogen bonds or salt bridges between polar groups and loss of hydrophobic interactions. This study is intended as a foundation for future work that will identify individual parameters in each molecular model that can be modified to improve their representations of protein structure and thermodynamics.