scholarly journals Testing the Limitations of MD-based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

2021 ◽  
Author(s):  
Jacek Kozuch ◽  
Samuel Schneider ◽  
Chu Zheng ◽  
Zhe Ji ◽  
Richard T Bradshaw ◽  
...  
Keyword(s):  
Electric Fields ◽  
Active Sites ◽  
Stark Effect ◽  
Force Fields ◽  
Direct Method ◽  
Md Simulations ◽  
Penicillin G ◽  
Conformational Sampling ◽  
Test Case ◽  
Water Models

<div>Non-covalent interactions underlie nearly all molecular processes in the condensed phase from solvation to</div><div>catalysis. Their quantification within a physically consistent framework remains challenging. Experimental vibrational Stark effect (VSE)-based solvatochromism can be combined with molecular dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid molecules and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach towards more complex (bio)molecules, such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based electric fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the electrics fields are correlated to conformation-dependent effects of the flexible PenG side-chain, including both local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in 3-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for experiment-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)molecules.</div>

scholarly journals Testing the Limitations of MD-based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

2021 ◽  
Author(s):  
Jacek Kozuch ◽  
Samuel Schneider ◽  
Chu Zheng ◽  
Zhe Ji ◽  
Richard T Bradshaw ◽  
...  
Keyword(s):  
Electric Fields ◽  
Active Sites ◽  
Stark Effect ◽  
Force Fields ◽  
Direct Method ◽  
Md Simulations ◽  
Penicillin G ◽  
Conformational Sampling ◽  
Test Case ◽  
Water Models

<div>Non-covalent interactions underlie nearly all molecular processes in the condensed phase from solvation to</div><div>catalysis. Their quantification within a physically consistent framework remains challenging. Experimental vibrational Stark effect (VSE)-based solvatochromism can be combined with molecular dynamics (MD) simulations to quantify the electrostatic forces in solute-solvent interactions for small rigid molecules and, by extension, when these solutes bind in enzyme active sites. While generalizing this approach towards more complex (bio)molecules, such as the conformationally flexible and charged penicillin G (PenG), we were surprised to observe inconsistencies in MD-based electric fields. Combining synthesis, VSE spectroscopy, and computational methods, we provide an intimate view on the origins of these discrepancies. We observe that the electrics fields are correlated to conformation-dependent effects of the flexible PenG side-chain, including both local solvation structure and solute conformational sampling in MD. Additionally, we identified that MD-based electric fields are consistently overestimated in 3-point water models in the vicinity of charged groups; this cannot be entirely ameliorated using polarizable force fields (AMOEBA) or advanced water models. This work demonstrates the value of the VSE as a direct method for experiment-guided refinements of MD force fields and establishes a general reductionist approach to calibrating vibrational probes for complex (bio)molecules.</div>

scholarly journals The Interplay of Electrostatics and Chemical Positioning in the Evolution of Antibiotic Resistance in TEM β-Lactamases

2021 ◽  
Author(s):  
Samuel H Schneider ◽  
Jacek Kozuch ◽  
Steven G Boxer
Keyword(s):  
Antibiotic Resistance ◽  
Electric Fields ◽  
Stark Effect ◽  
Structural Changes ◽  
Fitness Landscape ◽  
Md Simulations ◽  
Penicillin G ◽  
Modulate Function ◽  
Evolutionary Trajectory ◽  
Enzyme Active Site

The interplay of enzyme active site electrostatics and chemical positioning are important for understanding the origin(s) of enzyme catalysis and the design of novel catalysts. We reconstruct the evolutionary trajectory of TEM-1 β-lactamase to TEM-52 towards extended-spectrum activity to better understand the emergence of antibiotic resistance and to provide insights into the structure-function paradigm and non-covalent interactions involved in catalysis. Utilizing a detailed kinetic analysis and the vibrational Stark effect, we quantify the changes in rate and electric fields in the Michaelis and acyl-enzyme complexes for penicillin G and cefotaxime to ascertain the evolutionary role of electric fields to modulate function. These data are combined with MD simulations to interpret and quantify the substrate-dependent structural changes during evolution. We observe that evolution utilizes a large preorganized electric field and substrate-dependent chemical positioning to facilitate catalysis. This governs the evolvability, substrate promiscuity, and protein fitness landscape in TEM β-lactamase antibiotic resistance.

scholarly journals Testing the Limitations of MD-Based Local Electric Fields Using the Vibrational Stark Effect in Solution: Penicillin G as a Test Case

2021 ◽  
Author(s):  
Jacek Kozuch ◽  
Samuel H. Schneider ◽  
Chu Zheng ◽  
Zhe Ji ◽  
Richard T. Bradshaw ◽  
...  
Keyword(s):  
Electric Fields ◽  
Stark Effect ◽  
Penicillin G ◽  
Test Case

scholarly journals The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?

2020 ◽  
Author(s):  
Richard T Bradshaw ◽  
Jacek Dziedzic ◽  
Chris-Kriton Skylaris ◽  
Jonathan W. Essex
Keyword(s):  
Electric Fields ◽  
Active Sites ◽  
Catalytic Mechanism ◽  
Force Fields ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Polarizable Force Field ◽  
Polarizable Force Fields ◽  
Protein Active Sites ◽  
Dynamics Simulations

<div><div><div><p>Preorganization of large, directionally oriented, electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanism in many enzymes, and may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here we evaluate the ability of the AMOEBA polarizable force field, as well as the additive Amber ff14SB and Charmm C36m models, to describe the electric fields present inside the active site of the peptidyl-prolyl isomerase cyclophilin A. We compare the molecular mechanical electric fields to those calculated with a fully first principles quantum mechanical (QM) representation of the protein, solvent, and ions, and find that AMOEBA consistently shows far greater correlation with the QM electric fields than either of the additive force fields tested. Catalytically-relevant fields calculated with AMOEBA were typically smaller than those observed with additive potentials, but were generally consistent with an electrostatically-driven mechanism for catalysis. Our results highlight the accuracy and the potential advantages of using polarizable force fields in systems where accurate electrostatics may be crucial for providing mechanistic insights.</p></div></div></div>

scholarly journals Supramolecular Stark Effect in Host-Guest Complexes via Charge Density Analysis

2014 ◽  
Vol 70 (a1) ◽  
pp. C674-C674
Author(s):  
Sajesh Thomas ◽  
Rebecca Fuller ◽  
Alexandre Sobolev ◽  
Philip Schauer ◽  
Simon Grabowsky ◽  
...  
Keyword(s):  
Electric Field ◽  
Charge Density ◽  
Electric Fields ◽  
Active Sites ◽  
Stark Effect ◽  
Dipole Moments ◽  
Covalent Bonds ◽  
Guest Molecules ◽  
Density Mapping ◽  
Density Analysis

The effect of an electric field on the vibrational spectra, the Vibrational Stark Effect (VSE), has been utilized extensively to probe the local electric field in the active sites of enzymes [1, 2]. For this reason, the electric field and consequent polarization effects induced by a supramolecular host system upon its guest molecules attain special interest due to the implications for various biological processes. Although the host-guest chemistry of crown ether complexes and clathrates is of fundamental importance in supramolecular chemistry, many of these multicomponent systems have yet to be explored in detail using modern techniques [3]. In this direction, the electrostatic features associated with the host-guest interactions in the inclusion complexes of halogenated acetonitriles and formamide with 18-crown-6 host molecules have been analyzed in terms of their experimental charge density distribution. The charge density models provide estimates of the molecular dipole moment enhancements which correlate with the simulated values of dipole moments under electric field. The accurate electron density mapping using the multipole formalism also enable the estimation of the electric field experienced by the guest molecules. The electric field vectors thus obtained were utilized to estimate the vibrational stark effect in the nitrile (-C≡N) and carbonyl (C=O) stretching frequencies of the guest molecules via quantum chemical calculations in gas phase. The results of these calculations indicate remarkable elongation of C≡N and C=O bonds due to the electric fields. The electronic polarization in these covalent bonds induced by the field manifests as notable red shifts in their characteristic vibrational frequencies. These results derived from the charge densities are further supported by FT-IR experiments and thus establish the significance of a phenomenon that could be termed as the "supramolecular Stark effect" in crystal environment.

scholarly journals Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations

2020 ◽  
Author(s):  
Suman Samantray ◽  
Feng Yin ◽  
Batuhan Kav ◽  
Birgit Strodel
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Intrinsically Disordered Proteins ◽  
Force Fields ◽  
Md Simulations ◽  
Peptide Sequence ◽  
Disordered Proteins ◽  
Test Case ◽  
Peptide Aggregation ◽  
Intrinsically Disordered

AbstractThe progress towards understanding the molecular basis of Alzheimers’s disease is strongly connected to elucidating the early aggregation events of the amyloid-β (Aβ) peptide. Molecular dynamics (MD) simulations provide a viable technique to study the aggregation of Aβ into oligomers with high spatial and temporal resolution. However, the results of an MD simulation can only be as good as the underlying force field. A recent study by our group showed that none of the force fields tested can distinguish between aggregation-prone and non-aggregating peptide sequences, producing the same and in most cases too fast aggregation kinetics for all peptides. Since then, new force fields specially designed for intrinsically disordered proteins such as Aβ were developed. Here, we assess the applicability of these new force fields to studying peptide aggregation using the Aβ16−22 peptide and mutations of it as test case. We investigate their performance in modeling the monomeric state, the aggregation into oligomers, and the stability of the aggregation end product, i.e., the fibrillar state. A main finding is that changing the force field has a stronger effect on the simulated aggregation pathway than changing the peptide sequence. Also the new force fields are not able to reproduce the experimental aggregation propensity order of the peptides. Dissecting the various energy contributions shows that AMBER99SB-disp overestimates the interactions between the peptides and water, thereby inhibiting peptide aggregation. More promising results are obtained with CHARMM36m and especially its version with increased protein–water interactions. It is thus recommended to use this force field for peptide aggregation simulations and base future reparameterizations on it.

scholarly journals The Role of Electrostatics in Enzymes: Do Biomolecular Force Fields Reflect Protein Electric Fields?

2020 ◽  
Author(s):  
Richard T Bradshaw ◽  
Jacek Dziedzic ◽  
Chris-Kriton Skylaris ◽  
Jonathan W. Essex
Keyword(s):  
Electric Fields ◽  
Active Sites ◽  
Catalytic Mechanism ◽  
Force Fields ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Polarizable Force Field ◽  
Polarizable Force Fields ◽  
Protein Active Sites ◽  
Dynamics Simulations

<div><div><div><p>Preorganization of large, directionally oriented, electric fields inside protein active sites has been proposed as a crucial contributor to catalytic mechanism in many enzymes, and may be efficiently investigated at the atomistic level with molecular dynamics simulations. Here we evaluate the ability of the AMOEBA polarizable force field, as well as the additive Amber ff14SB and Charmm C36m models, to describe the electric fields present inside the active site of the peptidyl-prolyl isomerase cyclophilin A. We compare the molecular mechanical electric fields to those calculated with a fully first principles quantum mechanical (QM) representation of the protein, solvent, and ions, and find that AMOEBA consistently shows far greater correlation with the QM electric fields than either of the additive force fields tested. Catalytically-relevant fields calculated with AMOEBA were typically smaller than those observed with additive potentials, but were generally consistent with an electrostatically-driven mechanism for catalysis. Our results highlight the accuracy and the potential advantages of using polarizable force fields in systems where accurate electrostatics may be crucial for providing mechanistic insights.</p></div></div></div>

scholarly journals On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 99
Author(s):  
Cristian Privat ◽  
Sergio Madurga ◽  
Francesc Mas ◽  
Jaime Rubio-Martínez
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Md Simulations ◽  
Point Of View ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Protonation State ◽  
Constant Ph ◽  
Biochemical Systems ◽  
Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

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