Hybrid Models for Combined Quantum Mechanical and Molecular Mechanical Approaches

Bakowies, Dirk; Thiel, Walter

doi:10.1021/jp9536514

Cited by 1,187 publications

(1,128 citation statements)

References 111 publications

Supporting

Mentioning

1,113

Contrasting

Unclassified

Order By: Relevance

“…(3) can be effectively approximated by using the linear response approximation (LRA) treatment 41 : (4) where ΔG cav is the solvation free energy of the nonpolar neutral form of the solute. This term consist of two parts describing hydrophobic and van der Waals free energy of cavity, which are not included in the first two terms of Eq.…”

Section: Methodsmentioning

confidence: 99%

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

et al. 2008

View full text Add to dashboard Cite

Reliable studies of enzymatic reactions by combined quantum mechanical /molecular mechanics (QM(ai)/MM) approaches, with an ab initio description of the quantum region, presents a major challenge to computational chemists. The main problem is the need for very large computer time to evaluate the QM energy, which in turn makes it extremely challenging to perform proper configurational sampling. One of the most obvious options for accelerating QM/MM simulations is the use of an average solvent potential. In fact the idea of using an average solvent potential is rather obvious and has implicitly been used in Langevin dipole / QM calculations. However, in the case of explicit solvent models the practical implementations are more challenging and the accuracy of the averaging approach has not been validated. The present study introduces the average effect of the fluctuating solvent charges by using equivalent charge distributions, which are updated every m steps. Several models are evaluated in terms of the resulting accuracy and efficiency. The most effective model divides the system into an inner region with N explicit solvent atoms and an external region with two effective charges. Different models are considered in terms of the division of the solvent system and the update frequency. Another key element of our approach is the use of the free energy perturbation (FEP) and/or linear response approximation (LRA) treatments that guarantees the evaluation of the rigorous solvation free energy. Special attention is paid to the convergence of the calculated solvation free energies and the corresponding solute polarization. The performance of the method is examined by evaluating the solvation of a water molecule and a formate ion in water and also the dipole moment of water in water solution. Remarkably, it is found that different averaging procedures eventually converge to the same value but some protocols provide optimal ways of obtaining the final QM(ai)/MM converged results. The current method can provide computational time saving of 1000 for properly converging simulations relative to calculations that evaluate the QM(ai)/MM energy every time step. A specialized version of our approach that starts with a classical FEP charging and then evaluates the free energy of moving from the classical potential to the QM/ MM potential appears to be particularly effective. This approach should provide a very powerful tool for QM(ai)/MM evaluation of solvation free energies in aqueous solutions and proteins.

show abstract

Section: Methodsmentioning

confidence: 99%

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

et al. 2008

View full text Add to dashboard Cite

show abstract

“…40 An electrostatic embedding scheme was applied. 41 Partial atomic charges for the vanadate moiety were created using Weinhold natural population analysis (NPA) 42 from gas-phase models optimized at the RI-BP86/AE1 level of theory, see SI. The residues within 10 Å of the vanadium cofactor were included in the active MM region.…”

Section: Unprotonatedmentioning

confidence: 99%

⁵¹V NMR Chemical Shifts Calculated from QM/MM Models of Peroxo Forms of Vanadium Haloperoxidases

et al. 2009

Self Cite

View full text Add to dashboard Cite

“…[33][34][35] No electrostatic cut-offs were employed in the QM/MM calculations. Electrostatic embedding [36] with the charge-shift scheme [29,37] was used to couple the QM and MM regions. Full details of the computational methodology employed in this study are available in the Supporting Information.…”

Section: Introductionmentioning

confidence: 99%

Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Fürstner

Kirk

Fenster

et al. 2006

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Deliberate digression from the blueprint of the total syntheses of latrunculin A (1) and latrunculin B (2) reported in the accompanying paper allowed for the preparation of a focused library of “latrunculin‐like” compounds, in which all characteristic structural elements of these macrolides were subject to pertinent molecular editing. Although all previously reported derivatives of 1 and 2 were essentially devoid of any actin‐binding capacity, the synthetic compounds presented herein remain fully functional. One of the designer molecules with a relaxed macrocyclic backbone, that is compound 44, even surpasses latrunculin B in its effect on actin while being much easier to prepare. This favorable result highlights the power of “diverted total synthesis” as compared to the much more widely practiced chemical modification of a given lead compound by conventional functional group interconversion. A computational study was carried out to rationalize the observed effects. The analysis of the structure of the binding site occupied by the individual ligands on the G‐actin host shows that latrunculin A and 44 both have similar hydrogen‐bond network strengths and present similar ligand distortion. In contrast, the H‐bond network is weaker for latrunculin B and the distortion of the ligand from its optimum geometry is larger. From this, one may expect that the binding ability follows the order 1 ≥ 44 > 2, which is in accord with the experimental data. Furthermore, the biological results provide detailed insights into structure/activity relationships characteristic for the latrunculin family. Thus, it is demonstrated that the highly conserved thiazolidinone ring of the natural products can be replaced by an oxazolidinone moiety, and that inversion of the configuration at C16 (latrunculin B numbering) is also well accommodated. From a purely chemical perspective, this study attests to the maturity of ring‐closing alkyne metathesis (RCAM) catalyzed by a molybdenum alkylidyne complex generated in situ, which constitutes a valuable tool for advanced organic synthesis and natural product chemistry.

show abstract

Hybrid Models for Combined Quantum Mechanical and Molecular Mechanical Approaches

Cited by 1,187 publications

References 111 publications

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

⁵¹V NMR Chemical Shifts Calculated from QM/MM Models of Peroxo Forms of Vanadium Haloperoxidases

Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Contact Info

Product

Resources

About

Hybrid Models for Combined Quantum Mechanical and Molecular Mechanical Approaches

Cited by 1,187 publications

References 111 publications

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

Accelerating QM/MM Free Energy Calculations: Representing the Surroundings by an Updated Mean Charge Distribution

51V NMR Chemical Shifts Calculated from QM/MM Models of Peroxo Forms of Vanadium Haloperoxidases

Latrunculin Analogues with Improved Biological Profiles by “Diverted Total Synthesis”: Preparation, Evaluation, and Computational Analysis

Contact Info

Product

Resources

About

⁵¹V NMR Chemical Shifts Calculated from QM/MM Models of Peroxo Forms of Vanadium Haloperoxidases