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Full-Text Articles in Physical Sciences and Mathematics
Grotthuss Molecular Dynamics Simulations For Modeling Proton Hopping In Electrosprayed Water Droplets., Lars Konermann, Scott Kim
Grotthuss Molecular Dynamics Simulations For Modeling Proton Hopping In Electrosprayed Water Droplets., Lars Konermann, Scott Kim
Chemistry Publications
Excess protons in water exhibit unique transport properties because they can rapidly hop along H-bonded water wires. Considerable progress has been made in unraveling this Grotthuss diffusion mechanism using quantum mechanical-based computational techniques. Unfortunately, high computational cost tends to restrict those techniques to small systems and short times. Molecular dynamics (MD) simulations can be applied to much larger systems and longer time windows. However, standard MD methods do not permit the dissociation/formation of covalent bonds, such that Grotthuss diffusion cannot be captured. Here, we bridge this gap by combining atomistic MD simulations (using Gromacs and TIP4P/2005 water) with proton hopping. …
Formation Of Gaseous Peptide Ions From Electrospray Droplets: Competition Between The Ion Evaporation Mechanism And Charged Residue Mechanism., Elnaz Aliyari, Lars Konermann
Formation Of Gaseous Peptide Ions From Electrospray Droplets: Competition Between The Ion Evaporation Mechanism And Charged Residue Mechanism., Elnaz Aliyari, Lars Konermann
Chemistry Publications
The transfer of peptide ions from solution into the gas phase by electrospray ionization (ESI) is an integral component of mass spectrometry (MS)-based proteomics. The mechanisms whereby gaseous peptide ions are released from charged ESI nanodroplets remain unclear. This is in contrast to intact protein ESI, which has been the focus of detailed investigations using molecular dynamics (MD) simulations and other methods. Under acidic liquid chromatography/MS conditions, many peptides carry a solution charge of 3+ or 2+. Because of this pre-existing charge and their relatively small size, prevailing views suggest that peptides follow the ion evaporation mechanism (IEM). The IEM …
Mechanism Of Thermal Protein Aggregation: Experiments And Molecular Dynamics Simulations On The High-Temperature Behavior Of Myoglobin., Yuen Ki Ng, Nastaran N Tajoddin, Pablo M Scrosati, Lars Konermann
Mechanism Of Thermal Protein Aggregation: Experiments And Molecular Dynamics Simulations On The High-Temperature Behavior Of Myoglobin., Yuen Ki Ng, Nastaran N Tajoddin, Pablo M Scrosati, Lars Konermann
Chemistry Publications
Proteins that encounter unfavorable solvent conditions are prone to aggregation, a phenomenon that remains poorly understood. This work focuses on myoglobin (Mb) as a model protein. Upon heating, Mb produces amorphous aggregates. Thermal unfolding experiments at low concentration (where aggregation is negligible), along with centrifugation assays, imply that Mb aggregation proceeds via globally unfolded conformers. This contrasts studies on other proteins that emphasized the role of partially folded structures as aggregate precursors. Molecular dynamics (MD) simulations were performed to gain insights into the mechanism by which heat-unfolded Mb molecules associate with one another. A prerequisite for these simulations was the …
Atomistic Insights Into The Formation Of Nonspecific Protein Complexes During Electrospray Ionization., Elnaz Aliyari, Lars Konermann
Atomistic Insights Into The Formation Of Nonspecific Protein Complexes During Electrospray Ionization., Elnaz Aliyari, Lars Konermann
Chemistry Publications
Native electrospray ionization (ESI)-mass spectrometry (MS) is widely used for the detection and characterization of multi-protein complexes. A well-known problem with this approach is the possible occurrence of nonspecific protein clustering in the ESI plume. This effect can distort the results of binding affinity measurements, and it can even generate gas-phase complexes from proteins that are strictly monomeric in bulk solution. By combining experiments and molecular dynamics (MD) simulations, the current work for the first time provides detailed insights into the ESI clustering of proteins. Using ubiquitin as a model system, we demonstrate how the entrapment of more than one …
Keap1 Cancer Mutants: A Large-Scale Molecular Dynamics Study Of Protein Stability., Carter J Wilson, Megan Chang, Mikko Karttunen, Wing-Yiu Choy
Keap1 Cancer Mutants: A Large-Scale Molecular Dynamics Study Of Protein Stability., Carter J Wilson, Megan Chang, Mikko Karttunen, Wing-Yiu Choy
Chemistry Publications
We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise …
Mobile Protons Limit The Stability Of Salt Bridges In The Gas Phase: Implications For The Structures Of Electrosprayed Protein Ions., Lars Konermann, Elnaz Aliyari, Justin H Lee
Mobile Protons Limit The Stability Of Salt Bridges In The Gas Phase: Implications For The Structures Of Electrosprayed Protein Ions., Lars Konermann, Elnaz Aliyari, Justin H Lee
Chemistry Publications
Electrosprayed protein ions can retain native-like conformations. The intramolecular contacts that stabilize these compact gas-phase structures remain poorly understood. Recent work has uncovered abundant salt bridges in electrosprayed proteins. Salt bridges are zwitterionic BH+/A- contacts. The low dielectric constant in the vacuum strengthens electrostatic interactions, suggesting that salt bridges could be a key contributor to the retention of compact protein structures. A problem with this assertion is that H+ are mobile, such that H+ transfer can convert salt bridges into neutral B0/HA0 contacts. This possible salt bridge annihilation puts into question the …
Interrogating The Quaternary Structure Of Noncanonical Hemoglobin Complexes By Electrospray Mass Spectrometry And Collision-Induced Dissociation., Alexander I M Sever, Victor Yin, Lars Konermann
Interrogating The Quaternary Structure Of Noncanonical Hemoglobin Complexes By Electrospray Mass Spectrometry And Collision-Induced Dissociation., Alexander I M Sever, Victor Yin, Lars Konermann
Chemistry Publications
Various activation methods are available for the fragmentation of gaseous protein complexes produced by electrospray ionization (ESI). Such experiments can potentially yield insights into quaternary structure. Collision-induced dissociation (CID) is the most widely used fragmentation technique. Unfortunately, CID of protein complexes is dominated by the ejection of highly charged monomers, a process that does not yield any structural insights. Using hemoglobin (Hb) as a model system, this work examines under what conditions CID generates structurally informative subcomplexes. Native ESI mainly produced tetrameric Hb ions. In addition, "noncanonical" hexameric and octameric complexes were observed. CID of all these species [(αβ)2 …
Formation Of Gaseous Proteins Via The Ion Evaporation Model (Iem) In Electrospray Mass Spectrometry., Elnaz Aliyari, Lars Konermann
Formation Of Gaseous Proteins Via The Ion Evaporation Model (Iem) In Electrospray Mass Spectrometry., Elnaz Aliyari, Lars Konermann
Chemistry Publications
The mechanisms whereby protein ions are released into the gas phase from charged droplets during electrospray ionization (ESI) continue to be controversial. Several pathways have been proposed. For native ESI the charged residue model (CRM) is favored; it entails the liberation of proteins via solvent evaporation to dryness. Unfolded proteins likely follow the chain ejection model (CEM), which involves the gradual expulsion of stretched-out chains from the droplet. According to the ion evaporation model (IEM) ions undergo electrostatically driven desorption from the droplet surface. The IEM is well supported for small precharged species such as Na+. However, it …
Gas Phase Protein Folding Triggered By Proton Stripping Generates Inside-Out Structures: A Molecular Dynamics Simulation Study., Alexander I M Sever, Lars Konermann
Gas Phase Protein Folding Triggered By Proton Stripping Generates Inside-Out Structures: A Molecular Dynamics Simulation Study., Alexander I M Sever, Lars Konermann
Chemistry Publications
The properties of electrosprayed protein ions continue to be enigmatic, owing to the absence of high-resolution structure determination methods in the gas phase. There is considerable evidence that under properly optimized conditions these ions preserve solution-like conformations and interactions. However, it is unlikely that these solution-like conformers represent the "intrinsic" structural preferences of gaseous proteins. In an effort to uncover what such intrinsically preferred conformers might look like, we performed molecular dynamics (MD) simulations of gaseous ubiquitin. Our work was inspired by recent gas phase experiments, where highly extended 13+ ubiquitin ions were transformed to compact 3+ species by proton …
Enhancing Protein Electrospray Charge States By Multivalent Metal Ions: Mechanistic Insights From Md Simulations And Mass Spectrometry Experiments., Leanne M Martin, Lars Konermann
Enhancing Protein Electrospray Charge States By Multivalent Metal Ions: Mechanistic Insights From Md Simulations And Mass Spectrometry Experiments., Leanne M Martin, Lars Konermann
Chemistry Publications
The structure and reactivity of electrosprayed protein ions is governed by their net charge. Native proteins in non-denaturing aqueous solutions produce low charge states. More highly charged ions are formed when electrospraying proteins that are unfolded and/or exposed to organic supercharging agents. Numerous studies have explored the electrospray process under these various conditions. One phenomenon that has received surprisingly little attention is the charge enhancement caused by multivalent metal ions such as La3+ when electrospraying proteins out of non-denaturing solutions. Here, we conducted mass spectrometry and ion mobility spectrometry experiments, in combination with molecular dynamics (MD) simulations, to uncover …
Testing The Robustness Of Solution Force Fields For Md Simulations On Gaseous Protein Ions., Justin H Lee, Katja Pollert, Lars Konermann
Testing The Robustness Of Solution Force Fields For Md Simulations On Gaseous Protein Ions., Justin H Lee, Katja Pollert, Lars Konermann
Chemistry Publications
It is believed that electrosprayed proteins and protein complexes can retain solution-like conformations in the gas phase. However, the lack of high-resolution structure determination methods for gaseous protein ions implies that their properties remain poorly understood. Many practitioners tackle this difficulty by complementing mass spectrometry-based experiments with molecular dynamics (MD) simulations. It is a potential problem that the standard MD force fields used for this purpose (such as OPLS-AA/L and CHARMM) were optimized for solution conditions. The question whether these force fields produce meaningful gas-phase data has received surprisingly little attention. Standard force fields are overpolarized to account for an …
Mechanism Of Electrospray Supercharging For Unfolded Proteins: Solvent-Mediated Stabilization Of Protonated Sites During Chain Ejection., Insa Peters, Haidy Metwally, Lars Konermann
Mechanism Of Electrospray Supercharging For Unfolded Proteins: Solvent-Mediated Stabilization Of Protonated Sites During Chain Ejection., Insa Peters, Haidy Metwally, Lars Konermann
Chemistry Publications
Proteins that are unfolded in solution produce higher charge states during electrospray ionization (ESI) than their natively folded counterparts. Protein charge states can be further increased by the addition of supercharging agents (SCAs) such as sulfolane. The mechanism whereby these supercharged [M + zH] z+ ions are formed under unfolded conditions remains unclear. Here we employed a combination of mass spectrometry (MS), ion mobility spectrometry (IMS), and molecular dynamics (MD) simulations for probing the ESI mechanism under denatured supercharging conditions. ESI of acid-unfolded apo-myoglobin (aMb) in the presence of sulfolane produced charge states around 27+, all the way to fully …
Protein Ions Generated By Native Electrospray Ionization: Comparison Of Gas Phase, Solution, And Crystal Structures., Maryam Bakhtiari, Lars Konermann
Protein Ions Generated By Native Electrospray Ionization: Comparison Of Gas Phase, Solution, And Crystal Structures., Maryam Bakhtiari, Lars Konermann
Chemistry Publications
Experiments and molecular dynamics (MD) simulations in the literature indicate that gaseous proteins generated by electrospray ionization (ESI) can retain native-like structures. However, the exact properties of these ions remain to be explored. Focusing on ubiquitin and lysozyme, we examined several pertinent questions. (1) We applied solvent MD runs to test whether the X-ray structures of both proteins are affected by crystal packing. Main and side-chain orientations were retained in solution, providing a justification for the hitherto unscrutinized approach of relying on crystal data for "solution" versus gas-phase comparisons. (2) Most earlier gas-phase protein MD investigations employed short (ns) simulation …
Evidence For A Partially Stalled Γ Rotor In F, Angela Murcia Rios, Siavash Vahidi, Stanley D Dunn, Lars Konermann
Evidence For A Partially Stalled Γ Rotor In F, Angela Murcia Rios, Siavash Vahidi, Stanley D Dunn, Lars Konermann
Chemistry Publications
F1-ATPase uses ATP hydrolysis to drive rotation of the γ subunit. The γ C-terminal helix constitutes the rotor tip that is seated in an apical bearing formed by α3β3. It remains uncertain to what extent the γ conformation during rotation differs from that seen in rigid crystal structures. Existing models assume that the entire γ subunit participates in every rotation. Here we interrogated E. coli F1-ATPase by hydrogen-deuterium exchange (HDX) mass spectrometry. Rotation of γ caused greatly enhanced deuteration in the γ C-terminal helix. The HDX kinetics implied that most F1 …
Chain Ejection Model For Electrospray Ionization Of Unfolded Proteins: Evidence From Atomistic Simulations And Ion Mobility Spectrometry., Haidy Metwally, Quentin Duez, Lars Konermann
Chain Ejection Model For Electrospray Ionization Of Unfolded Proteins: Evidence From Atomistic Simulations And Ion Mobility Spectrometry., Haidy Metwally, Quentin Duez, Lars Konermann
Chemistry Publications
The ion evaporation model (IEM) and the charged residue model (CRM) represent cornerstones of any discussion related to the mechanism of electrospray ionization (ESI). Molecular dynamics (MD) simulations have confirmed that small ions such as Na+ are ejected from the surface of aqueous ESI droplets (IEM), while folded proteins in native ESI are released by water evaporation to dryness (CRM). ESI of unfolded proteins yields [M + zH] z+ ions that are much more highly charged than their folded counterparts. A chain ejection model (CEM) has been proposed to account for the protein ESI behavior under such non-native conditions …
How To Run Molecular Dynamics Simulations On Electrospray Droplets And Gas Phase Proteins: Basic Guidelines And Selected Applications., Lars Konermann, Haidy Metwally, Robert G Mcallister, Vlad Popa
How To Run Molecular Dynamics Simulations On Electrospray Droplets And Gas Phase Proteins: Basic Guidelines And Selected Applications., Lars Konermann, Haidy Metwally, Robert G Mcallister, Vlad Popa
Chemistry Publications
The ability to transfer intact proteins and protein complexes into the gas phase by electrospray ionization (ESI) has opened up numerous mass spectrometry (MS)-based avenues for exploring biomolecular structure and function. However, many details regarding the ESI process and the properties of gaseous analyte ions are difficult to decipher when relying solely on experimental data. Molecular dynamics (MD) simulations can provide additional insights into the behavior of ESI droplets and protein ions. This review is geared primarily towards experimentalists who wish to adopt MD simulations as a complementary research tool. We touch on basic points such as force fields, the …
Crown Ether Effects On The Location Of Charge Carriers In Electrospray Droplets: Implications For The Mechanism Of Protein Charging And Supercharging., Haidy Metwally, Lars Konermann
Crown Ether Effects On The Location Of Charge Carriers In Electrospray Droplets: Implications For The Mechanism Of Protein Charging And Supercharging., Haidy Metwally, Lars Konermann
Chemistry Publications
"Native" electrospray ionization (ESI) mass spectrometry (MS) aims to transfer proteins from solution into the gas phase while maintaining solution-like structures and interactions. The ability to control the charge states of protein ions produced in these experiments is of considerable importance. Supercharging agents (SCAs) such as sulfolane greatly elevate charge states without significantly affecting the protein structure in bulk aqueous solution. The origin of native ESI supercharging remains contentious. According to one model, SCAs trigger unfolding within ESI droplets. In contrast, the "charge trapping model" envisions that SCAs impede the ejection of charge carriers (e.g., NH4+ or Na …
Molecular Dynamics Simulations On Gas-Phase Proteins With Mobile Protons: Inclusion Of All-Atom Charge Solvation., Lars Konermann
Molecular Dynamics Simulations On Gas-Phase Proteins With Mobile Protons: Inclusion Of All-Atom Charge Solvation., Lars Konermann
Chemistry Publications
Molecular dynamics (MD) simulations have become a key tool for examining the properties of electrosprayed protein ions. Traditional force fields employ static charges on titratable sites, whereas in reality, protons are highly mobile in gas-phase proteins. Earlier studies tackled this problem by adjusting charge patterns during MD runs. Within those algorithms, proton redistribution was subject to energy minimization, taking into account electrostatic and proton affinity contributions. However, those earlier approaches described (de)protonated moieties as point charges, neglecting charge solvation, which is highly prevalent in the gas phase. Here, we describe a mobile proton algorithm that considers the electrostatic contributions from …
Calcium-Mediated Control Of S100 Proteins: Allosteric Communication Via An Agitator/Signal Blocking Mechanism., Yiming Xiao, Gary S Shaw, Lars Konermann
Calcium-Mediated Control Of S100 Proteins: Allosteric Communication Via An Agitator/Signal Blocking Mechanism., Yiming Xiao, Gary S Shaw, Lars Konermann
Chemistry Publications
Allosteric proteins possess dynamically coupled residues for the propagation of input signals to distant target binding sites. The input signals usually correspond to "effector is present" or "effector is not present". Many aspects of allosteric regulation remain incompletely understood. This work focused on S100A11, a dimeric EF-hand protein with two hydrophobic target binding sites. An annexin peptide (Ax) served as the target. Target binding is allosterically controlled by Ca2+ over a distance of ∼26 Å. Ca2+ promotes formation of a [Ca4 S100 Ax2] complex, where the Ax peptides are accommodated between helices III/IV and III'/IV'. …