More Like this

1. Absolute Protein Binding Free Energy Simulations for Ligands with Multiple Poses, a Thermodynamic Path That Avoids Exhaustive Enumeration of the Poses

   https://doi.org/10.1002/jcc.26078  

   Sakae, Yoshitake; Zhang, Bin W.; Levy, Ronald M.; Deng, Nanjie (October 2019, Journal of Computational Chemistry)

   We propose a free energy calculation method for receptor–ligand binding, which have multiple binding poses that avoids exhaustive enumeration of the poses. For systems with multiple binding poses, the standard procedure is to enumerate orientations of the binding poses, restrain the ligand to each orientation, and then, calculate the binding free energies for each binding pose. In this study, we modify a part of the thermodynamic cycle in order to sample a broader conformational space of the ligand in the binding site. This modification leads to more accurate free energy calculation without performing separate free energy simulations for each binding pose. We applied our modification to simple model host–guest systems as a test, which have only two binding poses, by using a single decoupling method (SDM) in implicit solvent. The results showed that the binding free energies obtained from our method without knowing the two binding poses were in good agreement with the benchmark results obtained by explicit enumeration of the binding poses. Our method is applicable to other alchemical binding free energy calculation methods such as the double decoupling method (DDM) in explicit solvent. We performed a calculation for a protein–ligand system with explicit solvent using our modified thermodynamic path. The results of the free energy simulation along our modified path were in good agreement with the results of conventional DDM, which requires a separate binding free energy calculation for each of the binding poses of the example of phenol binding to T4 lysozyme in explicit solvent. © 2019 Wiley Periodicals, Inc. 

   more » « less
2. Determining gas-phase chelation of zinc, cadmium, and copper cations with HisHis dipeptide using action spectroscopy and theoretical calculations

   https://doi.org/10.1016/j.ijms.2023.117154  

   Stevenson, Brandon C.; Berden, Giel; Martens, Jonathan; Oomens, Jos; Armentrout, P.B. (January 2024, International Journal of Mass Spectrometry)

   Using light generated by an infrared free electron laser, action spectroscopy was performed on doubly charged complexes of the metalated dipeptide histidyl-histidine (HisHis). Metal cations used were zinc, cadmium, and copper. Molecular dynamics and quantum-chemical calculations were used to screen a large number of conformers, whose theoretical infrared spectra were compared to the recorded action spectra of these metalated complexes. The zinc and cadmium spectra display dominant features associated with an iminol binding motif of the HisHis ligand, where the metal ion coordinates with both pros () nitrogens of the imidazole sidechains, the terminal carbonyl oxygen, and the backbone nitrogen for which the hydrogen ordinarily bound here has migrated to a carbonyl. The copper complex was difficult to assign to a single species, because a few predicted bands are absent from the experimental spectrum. The theoretical single point energies were also calculated for all structures examined, and DFT methods were found to describe the ion conformer populations in the case of the zinc and cadmium chelates better than the MP2 prediction. 

   more » « less
3. Coupling Monte Carlo, variational implicit solvation, and binary level-set for simulations of biomolecular binding

   Zhang, Z.; Ricci, C.; Fan, C.; Cheng, L.-T.; Li, B.; McCammon, J.A. (March 2021, Journal of chemical theory and computation)

   null (Ed.)

   We develop a hybrid approach that combines the Monte Carlo (MC)method, a variational implicit-solvent model (VISM), and a binary level-set method forthe simulation of biomolecular binding in an aqueous solvent. The solvation free energy for the biomolecular complex is estimated by minimizing the VISM free-energy functional of all possible solute−solvent interfaces that are used as dielectric boundaries. This functional consists of the solute volumetric, solute−solvent interfacial, solute−solvent van der Waals interaction, and electrostatic free energy. A technique of shifting the dielectric boundary is used to accurately predict the electrostatic part of the solvation free energy.Minimizing such a functional in each MC move is made possible by our new and fast binary level-set method. This method is based on the approximation of surface area by the convolution of an indicator function with a compactly supported kernel and is implemented by simple flips of numerical grid cells locally around the solute−solvent interface. We apply our approach to the p53-MDM2 system for which the two molecules are approximated by rigid bodies. Our efficient approach captures some of the poses before the final bound state. All atom molecular dynamics simulations with most of such poses quickly reach the final bound state.Our work is a new step toward realistic simulations of biomolecular interactions. With further improvement of coarse graining and MC sampling, and combined with other models, our hybrid approach can be used to study the free-energy landscape and kinetic pathways of ligand binding to proteins. 

   more » « less
4. Copper(I) SNS pincer complexes: Impact of ligand design and solvent coordination on conformer interconversion from spectroscopic and computational studies

   Lynn, M.A.; Miecznikowski, J.R.; Jasinski, J.P.; Kaur, M.; Mercado, B.Q.; Reinheimer, E.; Almanza, E.; Kharbouch, R.M.; Smith, M.R.; Zygmont, S.E.; et al (September 2019, Inorganica Chimica Acta)

   The syntheses and detailed characterizations (X-ray crystallography, NMR spectroscopy, cyclic voltammetry, infrared spectroscopy, electrospray mass spectrometry, and elemental analyses) of two new Cu(I) pincer complexes are reported. The pincer ligand coordinates through one nitrogen and two sulfur donor atoms and is based on bis-imidazole or bis-triazole precursors. These tridentate SNS ligands incorporate pyridine and thione-substituted imidazole or triazole functionalities with connecting methylene units that provide flexibility to the ligand backbone and enable high bite-angle binding. Variable temperature 1H NMR analysis of these complexes and of a similar zinc(II) SNS system shows that all are fluxional in solution and permits the determination of delta G double dagger and delta S double dagger. DFT calculations are used to model the fluxionality of these complexes and indicate that a coordinating solvent molecule can promote hemilability of the SNS ligand by lowering the energy barrier involved in the partial rotation of the methylene units. 

   more » « less
5. Solvent manipulation of the pre-reduction metal–ligand complex and particle-ligand binding for controlled synthesis of Pd nanoparticles

   https://doi.org/10.1039/d0nr06078j  

   Li, Wenhui; Taylor, Michael G.; Bayerl, Dylan; Mozaffari, Saeed; Dixit, Mudit; Ivanov, Sergei; Seifert, Soenke; Lee, Byeongdu; Shanaiah, Narasimhamurthy; Lu, Yubing; et al (January 2021, Nanoscale)

   null (Ed.)

   Understanding how to control the nucleation and growth rates is crucial for designing nanoparticles with specific sizes and shapes. In this study, we show that the nucleation and growth rates are correlated with the thermodynamics of metal–ligand/solvent binding for the pre-reduction complex and the surface of the nanoparticle, respectively. To obtain these correlations, we measured the nucleation and growth rates by in situ small angle X-ray scattering during the synthesis of colloidal Pd nanoparticles in the presence of trioctylphosphine in solvents of varying coordinating ability. The results show that the nucleation rate decreased, while the growth rate increased in the following order, toluene, piperidine, 3,4-lutidine and pyridine, leading to a large increase in the final nanoparticle size (from 1.4 nm in toluene to 5.0 nm in pyridine). Using density functional theory (DFT), complemented by 31 P nuclear magnetic resonance and X-ray absorption spectroscopy, we calculated the reduction Gibbs free energies of the solvent-dependent dominant pre-reduction complex and the solvent-nanoparticle binding energy. The results indicate that lower nucleation rates originate from solvent coordination which stabilizes the pre-reduction complex and increases its reduction free energy. At the same time, DFT calculations suggest that the solvent coordination affects the effective capping of the surface where stronger binding solvents slow the nanoparticle growth by lowering the number of active sites (not already bound by trioctylphosphine). The findings represent a promising advancement towards understanding the microscopic connection between the metal–ligand thermodynamic interactions and the kinetics of nucleation and growth to control the size of colloidal metal nanoparticles. 

   more » « less