Molecular Mechanics Software Research Articles

Atomic-Resolution Experimental Structural Biology and Molecular Dynamics Simulations of Hyaluronan and Its Complexes.

This review summarizes the atomic-resolution structural biology of hyaluronan and its complexes available in the Protein Data Bank, as well as published studies of atomic-resolution explicit-solvent molecular dynamics simulations on these and other hyaluronan and hyaluronan-containing systems. Advances in accurate molecular mechanics force fields, simulation methods and software, and computer hardware have supported a recent flourish in such simulations, such that the simulation publications now outnumber the structural biology publications by an order of magnitude. In addition to supplementing the experimental structural biology with computed dynamic and thermodynamic information, the molecular dynamics studies provide a wealth of atomic-resolution information on hyaluronan-containing systems for which there is no atomic-resolution structural biology either available or possible. Examples of these summarized in this review include hyaluronan pairing with other hyaluronan molecules and glycosaminoglycans, with ions, with proteins and peptides, with lipids, and with drugs and drug-like molecules. Despite limitations imposed by present-day computing resources on system size and simulation timescale, atomic-resolution explicit-solvent molecular dynamics simulations have been able to contribute significant insight into hyaluronan's flexibility and capacity for intra- and intermolecular non-covalent interactions.

Structure based virtual screening: Fast and slow

AbstractFor many decades virtual screening methods have provided a convenient and cost effective in silico solution in the early stages of drug discovery. In particular, molecular docking uses structural information to approximate protein–ligand recognition, providing valuable information for large chemical libraries at a fast pace with multiple success stories to validate the approach. Nevertheless, fast turnaround of results required assumptions and approximations which compromise the accuracy of these algorithms. On the other side of the spectrum, physical‐based molecular simulations offer more precise and realistic models of protein–ligand binding at the cost of being slower and requiring more expensive computing infrastructure. Both fast and slow approaches are useful and solve different aspects of the same problem. Here, we aim to review these approaches focusing on their capabilities, context of usage and limitations, presenting multiple examples along the way.This article is categorized under:Molecular and Statistical Mechanics > Molecular MechanicsSoftware > Molecular ModelingStructure and Mechanism > Computational Biochemistry and Biophysics

Testing for physical validity in molecular simulations.

Advances in recent years have made molecular dynamics (MD) and Monte Carlo (MC) simulations powerful tools in molecular-level research, allowing the prediction of experimental observables in the study of systems such as proteins, membranes, and polymeric materials. However, the quality of any prediction based on molecular dynamics results will strongly depend on the validity of underlying physical assumptions. Unphysical behavior of simulations can have significant influence on the results and reproducibility of these simulations, such as folding of proteins and DNA or properties of lipid bilayers determined by cutoff treatment, dynamics of peptides and polymers affected by the choice of thermostat, or liquid properties depending on the simulation time step. Motivated by such examples, we propose a two-fold approach to increase the robustness of molecular simulations. The first part of this approach involves tests which can be performed by the users of MD programs on their respective systems and setups. We present a number of tests of different complexity, ranging from simple post-processing analysis to more involved tests requiring additional simulations. These tests are shown to significantly increase the reliability of MD simulations by catching a number of common simulation errors violating physical assumptions, such as non-conservative integrators, deviations from the Boltzmann ensemble, and lack of ergodicity between degrees of freedom. To make the usage as easy as possible, we have developed an open-source and platform-independent Python library (https://physical-validation.readthedocs.io) implementing these tests. The second part of the approach involves testing for code correctness. While unphysical behavior can be due to poor or incompatible choices of parameters by the user, it can just as well originate in coding errors within the program. We therefore propose to include physical validation tests in the code-checking mechanism of MD software packages. We have implemented such a validation for the GROMACS software package, ensuring that every major release passes a number of physical sanity checks performed on selected representative systems before shipping. It is, to our knowledge, the first major molecular mechanics software package to run such validation routinely. The tests are, as the rest of the package, open source software, and can be adapted for other software packages.

Recent advances in dynamic docking for drug discovery

Molecular docking allows the evaluation of ligand‐target complementarity. This is the crucial first step in small‐molecule drug discovery. Over the last decade, increasing computer power and more efficient molecular dynamics (MD) software have prompted the use of MD for molecular docking. The resulting dynamic docking offers major improvements by (1) taking full account of the structural flexibility of the drug‐target system and (2) allowing the computation of the free energy and kinetics associated with drug binding. Here, we examine the recent advances in dynamic docking, while also considering the challenges and limitations that this powerful approach must overcome to impact fast‐paced drug discovery. WIREs Comput Mol Sci 2017, 7:e1320. doi: 10.1002/wcms.1320This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Mechanics Software > Molecular Modeling

Computer-Aided Molecular Design of Bis-phosphine Oxide Lanthanide Extractants.

Computer-aided molecular design and high-throughput screening of viable host architectures can significantly reduce the efforts in the design of novel ligands for efficient extraction of rare earth elements. This paper presents a computational approach to the deliberate design of bis-phosphine oxide host architectures that are structurally organized for complexation of trivalent lanthanides. Molecule building software, HostDesigner, was interfaced with molecular mechanics software, PCModel, providing a tool for generating and screening millions of potential R2(O)P-link-P(O)R2 ligand geometries. The molecular mechanics ranking of ligand structures is consistent with both the solution-phase free energies of complexation obtained with density functional theory and the performance of known bis-phosphine oxide extractants. For the case where the link is -CH2-, evaluation of the ligand geometry provides the first characterization of a steric origin for the "anomalous aryl strengthening" effect. The design approach has identified a number of novel bis-phosphine oxide ligands that are better organized for lanthanide complexation than previously studied examples.

De Novo Structure-Based Design of Bis-amidoxime Uranophiles

This paper presents a computational approach to the deliberate design of host architectures that recognize and bind specific guests. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, PCModel, providing a tool for generating and screening millions of potential structures. The efficacy of this computer-aided design methodology is illustrated with a search for bis-amidoxime chelates that are structurally organized for complexation with the uranyl cation.

SwissSidechain: a molecular and structural database of non-natural sidechains

Amino acids form the building blocks of all proteins. Naturally occurring amino acids are restricted to a few tens of sidechains, even when considering post-translational modifications and rare amino acids such as selenocysteine and pyrrolysine. However, the potential chemical diversity of amino acid sidechains is nearly infinite. Exploiting this diversity by using non-natural sidechains to expand the building blocks of proteins and peptides has recently found widespread applications in biochemistry, protein engineering and drug design. Despite these applications, there is currently no unified online bioinformatics resource for non-natural sidechains. With the SwissSidechain database (http://www.swisssidechain.ch), we offer a central and curated platform about non-natural sidechains for researchers in biochemistry, medicinal chemistry, protein engineering and molecular modeling. SwissSidechain provides biophysical, structural and molecular data for hundreds of commercially available non-natural amino acid sidechains, both in l- and d-configurations. The database can be easily browsed by sidechain names, families or physico-chemical properties. We also provide plugins to seamlessly insert non-natural sidechains into peptides and proteins using molecular visualization software, as well as topologies and parameters compatible with molecular mechanics software.

Expanding molecular modeling and design tools to non‐natural sidechains

Protein-protein interactions encode the wiring diagram of cellular signaling pathways and their deregulations underlie a variety of diseases, such as cancer. Inhibiting protein-protein interactions with peptide derivatives is a promising way to develop new biological and therapeutic tools. Here, we develop a general framework to computationally handle hundreds of non-natural amino acid sidechains and predict the effect of inserting them into peptides or proteins. We first generate all structural files (pdb and mol2), as well as parameters and topologies for standard molecular mechanics software (CHARMM and Gromacs). Accurate predictions of rotamer probabilities are provided using a novel combined knowledge and physics based strategy. Non-natural sidechains are useful to increase peptide ligand binding affinity. Our results obtained on non-natural mutants of a BCL9 peptide targeting beta-catenin show very good correlation between predicted and experimental binding free-energies, indicating that such predictions can be used to design new inhibitors. Data generated in this work, as well as PyMOL and UCSF Chimera plug-ins for user-friendly visualization of non-natural sidechains, are all available at http://www.swisssidechain.ch. Our results enable researchers to rapidly and efficiently work with hundreds of non-natural sidechains.

Calculated vibrational properties of pigments in protein binding sites

FTIR difference spectroscopy is widely used to probe molecular bonding interactions of protein-bound electron transfer cofactors. The technique is particularly attractive because it provides information on both neutral and radical cofactor states. Such dual information is not easily obtainable using other techniques. Although FTIR difference spectroscopy has been used to study cofactors in biological protein complexes, in nearly all cases interpretation of the spectra has been purely qualitative. Virtually no computational work has been undertaken in an attempt to model the spectra. To address this problem we have developed the use of ONIOM (our own N-layered integrated molecular Orbital+Molecular mechanics package) (quantum mechanical:molecular mechanics) methods to calculate FTIR difference spectra associated with protein-bound cofactors. As a specific example showing the utility of the approach we have calculated isotope edited FTIR difference spectra associated with unlabeled and labeled ubiquinones in the Q(A) binding site in Rhodobacter sphaeroides photosynthetic reaction centers. The calculated spectra are in remarkable agreement with experiment. Such agreement cannot be obtained by considering ubiquinone molecules in the gas phase or in solution. A calculation including the protein environment is required. The ONIOM calculated spectra agree well with experiment but indicate a very different interpretation of the experimental data compared to that proposed previously. In particular the calculations do not predict that one of the carbonyl groups of Q(A) is very strongly hydrogen bonded. We show that a computational-based interpretation of FTIR difference spectra associated with protein-bound cofactors is now possible. This approach will be applicable to FTIR studies of many cofactor-containing proteins.

Identification of Escherichia coli Mismatch-specific Uracil DNA Glycosylase as a Robust Xanthine DNA Glycosylase

The gene for the mismatch-specific uracil DNA glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the human thymine DNA glycosylase with activity against mismatched uracil base pairs. Examination of cell extracts led us to detect a previously unknown xanthine DNA glycosylase (XDG) activity in E. coli. DNA glycosylase assays with purified enzymes indicated the novel XDG activity is attributable to MUG. Here, we report a biochemical characterization of xanthine DNA glycosylase activity in MUG. The wild type MUG possesses more robust activity against xanthine than uracil and is active against all xanthine-containing DNA (C/X, T/X, G/X, A/X and single-stranded X). Analysis of potentials of mean force indicates that the double-stranded xanthine base pairs have a relatively narrow energetic difference in base flipping, whereas the tendency for uracil base flipping follows the order of C/U > G/U > T/U > A/U. Site-directed mutagenesis performed on conserved motifs revealed that Asn-140 and Ser-23 are important determinants for XDG activity in E. coli MUG. Molecular modeling and molecular dynamics simulations reveal distinct hydrogen-bonding patterns in the active site of E. coli MUG that account for the specificity differences between E. coli MUG and human thymine DNA glycosylase as well as that between the wild type MUG and the Asn-140 and Ser-23 mutants. This study underscores the role of the favorable binding interactions in modulating the specificity of DNA glycosylases.

A Combined Computational and Functional Approach Identifies New Residues Involved in pH-dependent Gating of ASIC1a

Acid-sensing ion channels (ASICs) are key receptors for extracellular protons. These neuronal nonvoltage-gated Na(+) channels are involved in learning, the expression of fear, neurodegeneration after ischemia, and pain sensation. We have applied a systematic approach to identify potential pH sensors in ASIC1a and to elucidate the mechanisms by which pH variations govern ASIC gating. We first calculated the pK(a) value of all extracellular His, Glu, and Asp residues using a Poisson-Boltzmann continuum approach, based on the ASIC three-dimensional structure, to identify candidate pH-sensing residues. The role of these residues was then assessed by site-directed mutagenesis and chemical modification, combined with functional analysis. The localization of putative pH-sensing residues suggests that pH changes control ASIC gating by protonation/deprotonation of many residues per subunit in different channel domains. Analysis of the function of residues in the palm domain close to the central vertical axis of the channel allowed for prediction of conformational changes of this region during gating. Our study provides a basis for the intrinsic ASIC pH dependence and describes an approach that can also be applied to the investigation of the mechanisms of the pH dependence of other proteins.

Application of Kihara parameters in conventional molecular force fields

While the Lennard-Jones function has been widely adopted in molecular mechanics for describing neutral non-bonded interatomic interactions, the Kihara potential possesses the flexibility of describing intermolecular energy. Due to the pervasiveness of the former and the flexibility of the latter, a set of conversion formulas is described herein for enabling molecular mechanics software to describe intermolecular energy via slight alteration to the Lennard-Jones function. In this paper it is shown that the combined imposition of equal force constant and equal equilibrium-to-dissociation energy integral enables a pair of Lennard-Jones indices to be obtained. Plotted results exhibit impeccable agreement. Such relations allow quick adoption of Kihara parameters of molecules to be applied in conventional molecular mechanics software by imal re-coding of the latter—thereby saving time and cost.

The variational explicit polarization potential and analytical first derivative of energy: Towards a next generation force field

A previous article proposed an electronic structure-based polarizable potential, called the explicit polarization (X-POL) potential, to treat many-body polarization and charge delocalization effects in polypeptides. Here, we present a variational version of the X-POL potential, in which the wave function of the entire molecular system is variationally optimized to yield the minimum total electronic energy. This allows the calculation of analytic gradients, a necessity for efficient molecular dynamics simulations. In this paper, the detailed derivations of the Fock matrix and analytic force are presented and discussed. The calculations involve a double self-consistent-field procedure in which the wave function of each fragment is self-consistently optimized in the presence of other fragments, and in addition the polarization of the entire system is self-consistently optimized. The variational X-POL potential has been implemented in the Chemistry at Harvard Molecular Mechanics (CHARMM) package and tested successfully for small model compounds.

Structure–olfactive threshold relationships for pyrazine derivatives

Structure-olfactive threshold relationships for 40 pyrazine derivatives have been studied by multivariate statistical analysis. Variable descriptors used to describe the molecules studied were obtained using molecular-mechanics software. A correlation coefficient of 0.82 was obtained when all the molecules were included in the model. When the model was established for closely related subsets of molecules, the correlation coefficients obtained were higher and the established models were bilinear. Such models allow the identification of optimal structures corresponding to low olfactive thresholds for the subsets studied. Surprisingly, we find that the optimum structures are included in the set of 40 molecules. The efficiency of the models was supported by the cross-validation technique, where the correlation coefficients were found to be good with respect to the precision of the values of the olfactive thresholds.

Quantum Mechanical Modeling of Self-Assembly and Photoinduced Electron Transfer in PNA-Based Artificial Living Organisms

In order to support the creation of both artificial living organisms in the USA LANL "Protocell Assembly" project and programmable nano-biorobots in the EU "Programmable Artificial Cell Evolution" project, we used quantum mechanical (QM), density functional theory (DFT), the semiempirical PM3 method, and molecular mechanics (MM) software to investigate various complex photosynthetic systems based on peptide nucleic acid (PNA) in a water environment. Quantum mechanical DFT PBEPBE simulations, including electron correlations, confirm that water molecules that surround all the photosynthetic complex of the LANL protoorganism are main constructing factors and stabilize this system consisting of: PNA fragment attached by covalent bond sensitizer 1,4-bis(N,N-dimethylamino)naphthalene molecule, lipid precursor molecule and fragment of lipid molecules mono layer. The absorption spectrum shift to the red wavelengths in the complex artificial protocell photosynthetic center might be used as the measure of the complexity of this system. The electron pi-pi* transitions in the first and third excited states are from HOMO and HOMO-1 located on the conjugated water molecules and sensitizer 1,4-bis(N,N-dimethylamino)naphthalene molecule to the LUMO of the lipid precursor molecule as calculated using the time dependent (TD) PBEPBE/6-31G model. Electron charge tunneling in the first and third excited states should induce metabolic photodissociation of the lipid precursor molecule because of localization of the transferred electron cloud on the head (waste) of the lipid precursor molecule. TD electron correlation PBEPBE/6-31G calculations show that in the different energies of excitation, the charge transfer tunneling is from sensitizer to lipid precursor and cytosine molecules. One should note that in a water solvent, the electron charge transfer pi-pi* transition in the fifth and sixth excited state is from the HOMO and HOMO-1 located on the sensitizer 1,4-bis(N,N-dimethylamino)naphthalene molecule to the LUMO+2 located on the cytosine-PNA fragment molecule. Investigation results indicate that strong back electron tunneling from the sensitizer 1,4-bis(N,N-dimethylamino)naphthalene molecule to the cytosine molecule in the LANL artificial photosynthetic system exists.

De Novo Structure-Based Design of Bisurea Hosts for Tetrahedral Oxoanion Guests

This paper presents a computational approach to the deliberate design of improved host architectures. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, GMMX, providing a tool for generating and screening millions of potential structures. The efficacy of this computer-aided design methodology is illustrated with a search for bisurea podands that are structurally organized for complexation with tetrahedral oxoanions.

Search for Improved Host Architectures: Application of de Novo Structure-Based Design and High-Throughput Screening Methods To Identify Optimal Building Blocks for Multidentate Ethers

This paper presents a computational approach to the deliberate design of improved host architectures. The approach, which involves the use of computer-aided design software, is illustrated by application to cation hosts containing multiple aliphatic ether oxygen binding sites. De novo molecule building software, HostDesigner, is interfaced with molecular mechanics software, GMMX, providing a tool for generating and screening millions of potential bidentate building block structures. Enhanced cation binding affinity can be achieved when highly organized building blocks are used to construct macrocyclic hosts.

Ethanol pretreatment effect and particle diameter issues on the adsorption of Candida rugosa lipase onto polypropylene powder

Lipase from Candida rugosa (CR) was adsorbed onto low-molecular-weight polypropylene powder (PP). Fourier transform infrared (FTIR), scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDX) techniques, and conversion yield of CR/PP-mediated-ethyl oleate synthesis in solvent-free media, demonstrated lipase adsorption onto PP and its affinity towards biggest polypropylene particles (590–1180μm). An ethanol pretreatment was assayed in order to decrease the hydrophobic nature of PP. Long periods of ethanol pretreatment led to immobilised particles with different average size and associated activity. Molecular mechanics software packages were used to study the interaction between polypropylene and CR’s lid.

MM3(96) CONFORMATIONAL ANALYSIS OF d-GLUCARAMIDE AND X-RAY CRYSTAL STRUCTURES OF THREE d-GLUCARIC ACID DERIVATIVES—MODELS FOR SYNTHETIC POLY(ALKYLENE d-GLUCARAMIDES)

An exhaustive conformational analysis of d-glucaramide was carried out using MM3(96) [MM3(96). Molecular Mechanics Software used with permission from N.L. Allinger; University of Georgia]. Nine torsion angles were each driven in increments of 120°, generating 19,683 starting conformations. Each conformation was then fully energy-minimized using MM3's block diagonal/full matrix optimization option at dielectric constants of both 3.5 and 6.5. Conformer populations were calculated based on the modeling results and calculated theoretical average 1H vicinal coupling constants were compared to experimental values obtained in D 2O solution. Crystal structures of three acyclic d-glucaric acid derivatives (N, N′-dimethyl- d-glucaramide, dipotassium d-glucarate, and sodium potassium d-glucarate) are reported. These structures and that of previously reported monopotassium glucarate correspond closely with model conformations that were within one kcal/mol of the global minimum.

Hybrid molecular mechanics: For effective crystal field method for modeling potential energy surfaces of transition metal complexes

AbstractThe effective crystal field (ECF) methodology previously developed for description of the electronic structure of transition metal complexes (TMCs) is combined with molecular mechanics (MM) formalism. In this way, a new method for calculations of potential energy surfaces of the Werner‐type TMC is developed. It is based on a combined quantum mechanics (QM)–MM approach with the ECF method taking part of the QM and advanced MM package MMPC developed for the metal ion complex computations and based on the CHARMM organic force field. The MM region consists of ligand atoms and metal ion coordination sphere, leaving out effects of d‐shell, while the QM region is limited to metal ion d‐shell. Crystal field matrix for the d‐shell is calculated with use of the local ECF method. It is shown that the procedure proposed reproduces with considerable accuracy geometry characteristics of values of the Fe(II) complexes with both mono‐ and polydentate ligands. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002