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Journal of Chemical Theory and... Jun 2022The sampling problem is one of the most widely studied topics in computational chemistry. While various methods exist for sampling along a set of reaction coordinates,...
The sampling problem is one of the most widely studied topics in computational chemistry. While various methods exist for sampling along a set of reaction coordinates, many require system-dependent hyperparameters to achieve maximum efficiency. In this work, we present an alchemical variation of adaptive sequential Monte Carlo (SMC), an irreversible importance resampling method that is part of a well-studied class of methods that have been used in various applications but have been underexplored in computational biophysics. Afterward, we apply alchemical SMC on a variety of test cases, including torsional rotations of solvated ligands (butene and a terphenyl derivative), translational and rotational movements of protein-bound ligands, and protein side chain rotation coupled to the ligand degrees of freedom (T4-lysozyme, protein tyrosine phosphatase 1B, and transforming growth factor β). We find that alchemical SMC is an efficient way to explore targeted degrees of freedom and can be applied to a variety of systems using the same hyperparameters to achieve a similar performance. Alchemical SMC is a promising tool for preparatory exploration of systems where long-timescale sampling of the entire system can be traded off against short-timescale sampling of a particular set of degrees of freedom over a population of conformers.
Topics: Ligands; Monte Carlo Method; Proteins
PubMed: 35588256
DOI: 10.1021/acs.jctc.1c01198 -
Journal of Chemical Information and... Nov 2021Rational drug design involves a task of finding ligands that would bind to a specific target protein. This work presents CHARMM-GUI that is an intuitive and interactive...
Rational drug design involves a task of finding ligands that would bind to a specific target protein. This work presents CHARMM-GUI that is an intuitive and interactive web-based tool to design virtual ligands that match the shape and chemical features of a given protein binding site. provides ligand modification capabilities with 3D visualization that allow researchers to modify and redesign virtual ligands while viewing how the protein-ligand interactions are affected. Virtual ligands can also be parameterized for further molecular dynamics (MD) simulations and free energy calculations. Using 8 targets from 8 different protein classes in the directory of useful decoys, enhanced (DUD-E) data set, we show that can produce similar ligands to the known active ligands in the crystal structures. also produces stable protein-ligand complex structures when tested using short MD simulations. We expect that can be a useful and user-friendly tool to design small molecules in any given potential ligand binding site on a protein of interest.
Topics: Binding Sites; Ligands; Molecular Dynamics Simulation; Protein Binding; Proteins
PubMed: 34757752
DOI: 10.1021/acs.jcim.1c01156 -
Molecules (Basel, Switzerland) Nov 2022The excellent π-accepting azodicarboxylic esters adcOR (R = Et, Pr, Bu, Bn (CH-CH) and Ph) and the piperidinyl amide derivative adcpip were used as bridging chelate...
The excellent π-accepting azodicarboxylic esters adcOR (R = Et, Pr, Bu, Bn (CH-CH) and Ph) and the piperidinyl amide derivative adcpip were used as bridging chelate ligands in dinuclear Re(CO) complexes [{Re(CO)Cl}(µ-adcOR)] and [{Re(CO)Cl}(µ-adcpip)]. From the adcpip ligand the mononuclear derivatives [Re(CO)Cl(adcpip)] and [Re(CO)(PPh)(µ-adcpip)]Cl were also obtained. Optimised geometries from density functional theory (DFT) calculations show and isomers for the dinuclear -Re(CO) complexes at slightly different energies but they were not distinguishable from experimental IR or UV-Vis absorption spectroscopy. The electrochemistry of the adc complexes showed reduction potentials slightly below 0.0 V vs. the ferrocene/ferrocenium couple. Attempts to generate the radicals [{Re(CO)Cl}(µ-adcOR)] failed as they are inherently unstable, losing very probably first the Cl coligand and then rapidly cleaving one [Re(CO)] fragment. Consequently, we found signals in EPR very probably due to mononuclear radical complexes [Re(CO)(solv)(adc)]. The underlying Cl→solvent exchange was modelled for the mononuclear [Re(CO)Cl(adcpip)] using DFT calculations and showed a markedly enhanced Re-Cl labilisation for the reduced compared with the neutral complex. Both the easy reduction with potentials ranging roughly from -0.2 to -0.1 V for the adc ligands and the low-energy NIR absorptions in the 700 to 850 nm range place the adc ligands with their lowest-lying π* orbital being localised on the azo function, amongst comparable bridging chelate N^N coordinating ligands with low-lying π* orbitals of central azo, tetrazine or pyrazine functions. Comparative (TD)DFT-calculations on the Re(CO)Cl complexes of the adcpip ligand using the quite established basis set and functionals M06-2X/def2TZVP/LANL2DZ/CPCM(THF) and the more advanced TPSSh/def2-TZVP(+def2-ECP for Re)/CPCMC(THF) for single-point calculations with BP86/def2-TZVP(+def2-ECP for Re)/CPCMC(THF) optimised geometries showed a markedly better agreement of the latter with the experimental XRD, IR and UV-Vis absorption data.
Topics: Rhenium; Ligands; Spectrum Analysis; Electrochemistry
PubMed: 36500250
DOI: 10.3390/molecules27238159 -
Scientific Reports Aug 2023There are continuous efforts to elucidate the structure and biological functions of short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms reside more than...
There are continuous efforts to elucidate the structure and biological functions of short hydrogen bonds (SHBs), whose donor and acceptor heteroatoms reside more than 0.3 Å closer than the sum of their van der Waals radii. In this work, we evaluate 1070 atomic-resolution protein structures and characterize the common chemical features of SHBs formed between the side chains of amino acids and small molecule ligands. We then develop a machine learning assisted prediction of protein-ligand SHBs (MAPSHB-Ligand) model and reveal that the types of amino acids and ligand functional groups as well as the sequence of neighboring residues are essential factors that determine the class of protein-ligand hydrogen bonds. The MAPSHB-Ligand model and its implementation on our web server enable the effective identification of protein-ligand SHBs in proteins, which will facilitate the design of biomolecules and ligands that exploit these close contacts for enhanced functions.
Topics: Ligands; Hydrogen Bonding; Amino Acids; Antifibrinolytic Agents; Machine Learning
PubMed: 37612311
DOI: 10.1038/s41598-023-40614-7 -
Talanta Mar 2021The range of applications for aptamers, small oligonucleotide-based receptors binding to their targets with high specificity and affinity, has been steadily expanding....
The range of applications for aptamers, small oligonucleotide-based receptors binding to their targets with high specificity and affinity, has been steadily expanding. Our understanding of the mechanisms governing aptamer-ligand recognition and binding is however lagging, stymieing the progress in the rational design of new aptamers and optimization of the known ones. Here we demonstrate the capabilities and limitations of native ion mobility-mass spectrometry for the analysis of their higher-order structure and non-covalent interactions. A set of related cocaine-binding aptamers, displaying a range of folding properties and ligand binding affinities, was used as a case study in both positive and negative electrospray ionization modes. Using carefully controlled experimental conditions, we probed their conformational behavior and interactions with the high-affinity ligand quinine as a surrogate for cocaine. The ratios of bound and unbound aptamers in the mass spectra were used to rank them according to their apparent quinine-binding affinity, qualitatively matching the published ranking order. The arrival time differences between the free aptamer and aptamer-quinine complexes were consistent with a small ligand-induced conformational change, and found to inversely correlate with the affinity of binding. This mass spectrometry-based approach provides a fast and convenient way to study the molecular basis of aptamer-ligand recognition.
Topics: Aptamers, Nucleotide; Binding Sites; Ligands; Mass Spectrometry; Nucleic Acid Conformation
PubMed: 33379118
DOI: 10.1016/j.talanta.2020.121917 -
Molecules (Basel, Switzerland) Jul 2022For more than 60 years, in coordination chemistry (and since the beginning of the 21st century, in molecular nanotechnology, too), there has been very significant...
For more than 60 years, in coordination chemistry (and since the beginning of the 21st century, in molecular nanotechnology, too), there has been very significant interest in template synthesis reactions, in which the design of coordination compounds (metal complexes) with complex ligands is carried out not according to the classical scheme [metal ion + ligand → complex], but according to scheme [metal ion + "building blocks" of the future ligand (the so-called ligand synthons or ligsons) → complex] [...].
Topics: Coordination Complexes; Ligands; Metals
PubMed: 35956780
DOI: 10.3390/molecules27154829 -
ELife Mar 2022While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to...
While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent-exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decreases and relative hydrophobicity increases. Across a series of 13 inhibitor-bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from nuclear magnetic resonance studies suggesting that residual side-chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.
Topics: Binding Sites; Ligands; Protein Binding; Protein Conformation; Proteins
PubMed: 35312477
DOI: 10.7554/eLife.74114 -
Molecules (Basel, Switzerland) Mar 2023Mixed ligand complexes of Pd(II) and Cd(II) with -picolyl-amine dithiocarbamate (PAC-dtc) as primary ligand and tertiary phosphine ligand as secondary ligands have been...
Mixed ligand complexes of Pd(II) and Cd(II) with -picolyl-amine dithiocarbamate (PAC-dtc) as primary ligand and tertiary phosphine ligand as secondary ligands have been synthesized and characterized via elemental analysis, molar conductance, NMR (H and P), and IR techniques. The PAC-dtc ligand displayed in a monodentate fashion via sulfur atom whereas diphosphine ligands coordinated as a bidentate mode to afford a square planner around the Pd(II) ion or tetrahedral around the Cd(II) ion. Except for complexes [Cd(PAC-dtc)(dppe)] and [Cd(PAC-dtc)(PPh)], the prepared complexes showed significant antimicrobial activity when evaluated against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger. Moreover, DFT calculations were performed to investigate three complexes {[Pd(PAC-dtc)(dppe)](1), [Cd(PAC-dtc)(dppe)](2), [Cd(PAC-dtc)(PPh)](7)}, and their quantum parameters were evaluated using the Gaussian 09 program at the B3LYP/Lanl2dz theoretical level. The optimized structures of the three complexes were square planar and tetrahedral geometry. The calculated bond lengths and bond angles showed a slightly distorted tetrahedral geometry for [Cd(PAC-dtc)(dppe)](2) compared to [Cd(PAC-dtc)(PPh)](7) due to the ring constrain in the dppe ligand. Moreover, the [Pd(PAC-dtc)(dppe)](1) complex showed higher stability compared to and complexes which can be attributed to the higher back-donation of Pd(1) complex.
Topics: Cadmium; Ligands; Magnetic Resonance Spectroscopy; Coordination Complexes
PubMed: 36903550
DOI: 10.3390/molecules28052305 -
Pharmacological Reviews Mar 2009Ethanol exerts its biological actions through multiple receptors, including ion channels. Ion channels that are sensitive to pharmacologically relevant ethanol... (Review)
Review
Ethanol exerts its biological actions through multiple receptors, including ion channels. Ion channels that are sensitive to pharmacologically relevant ethanol concentrations constitute a heterogeneous set, including structurally unrelated proteins solely sharing the property that their gating is regulated by a ligand(s). Receptor desensitization is almost universal among these channels, and its modulation by ethanol may be a crucial aspect of alcohol pharmacology and effects in the body. We review the evidence documenting interactions between ethanol and ionotropic receptor desensitization, and the contribution of this interaction to overall ethanol action on channel function. In some cases, such as type 3 serotonin, nicotinic acetylcholine, GABA-A, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, ethanol actions on apparent desensitization play a significant role in acute drug action on receptor function. In a few cases, mutagenesis helped to identify different areas within a receptor protein that differentially sense n-alcohols, resulting in differential modulation of receptor desensitization. However, desensitization of a receptor is linked to a variety of biochemical processes that may alter protein conformation, such as the lipid microenvironment, post-translational channel modification, and channel subunit composition, the relative contribution of these processes to ethanol interactions with channel desensitization remains unclear. Understanding interactions between ethanol and ionotropic receptor desensitization may help to explain different ethanol actions 1) when ethanol is evaluated in vitro on cloned channel proteins, 2) under physiological or pathological conditions or in distinct cell domains with modified ligand concentration and/or receptor conformation. Finally, receptor desensitization is likely to participate in molecular and, possibly, behavioral tolerance to ethanol, which is thought to contribute to the risk of alcoholism.
Topics: Animals; Ethanol; Humans; Ion Channel Gating; Ion Channels; Ligands
PubMed: 19270242
DOI: 10.1124/pr.108.000430 -
Journal of Chemical Theory and... Feb 2023Ligand binding thermodynamics and kinetics are critical parameters for drug design. However, it has proven challenging to efficiently predict ligand binding...
Ligand binding thermodynamics and kinetics are critical parameters for drug design. However, it has proven challenging to efficiently predict ligand binding thermodynamics and kinetics from molecular simulations due to limited simulation timescales. Protein dynamics, especially in the ligand binding pocket, often plays an important role in ligand binding. Based on our previously developed Ligand Gaussian accelerated molecular dynamics (LiGaMD), here we present LiGaMD2 in which a selective boost potential was applied to both the ligand and protein residues in the binding pocket to improve sampling of ligand binding and dissociation. To validate the performance of LiGaMD2, the T4 lysozyme (T4L) mutants with open and closed pockets bound by different ligands were chosen as model systems. LiGaMD2 could efficiently capture repetitive ligand dissociation and binding within microsecond simulations of all T4L systems. The obtained ligand binding kinetic rates and free energies agreed well with available experimental values and previous modeling results. Therefore, LiGaMD2 provides an improved approach to sample opening of closed protein pockets for ligand dissociation and binding, thereby allowing for efficient calculations of ligand binding thermodynamics and kinetics.
Topics: Molecular Dynamics Simulation; Ligands; Proteins; Thermodynamics; Protein Binding; Kinetics
PubMed: 36706316
DOI: 10.1021/acs.jctc.2c01194