Accelerating Rare Dissociative Processes in Biomolecules Using Selectively Scaled MD Simulations

2019 ◽  
Vol 15 (11) ◽  
pp. 5817-5828 ◽  
Author(s):  
Indrajit Deb ◽  
Aaron T. Frank
Keyword(s):  
Md Simulations ◽  
Dissociative Processes

scholarly journals Accelerating Dissociative Events in Molecular Dynamics Simulations by Selective Potential Scaling

2019 ◽  
Author(s):  
Indrajit Deb ◽  
Aaron T. Frank
Keyword(s):  
Molecular Dynamics ◽  
Sampling Method ◽  
Potential Energy Function ◽  
Md Simulations ◽  
Cyclin Dependent Kinase ◽  
Enhanced Sampling ◽  
Free Energies ◽  
Biologically Relevant ◽  
Dynamics Simulations ◽  
Dissociative Processes

ABSTRACTMolecular dynamics (or MD) simulations can be a powerful tool for modeling complex dissociative processes such as ligand unbinding. However, many biologically relevant dissociative processes occur on timescales that far exceed the timescales of typical MD simulations. Here, we implement and apply an enhanced sampling method in which specific energy terms in the potential energy function are selectively “scaled” to accelerate dissociative events during simulations. Using ligand unbinding as an example of a complex dissociative process, we selectively scaled-up ligand-water interactions in an attempt to increase the rate of ligand unbinding. By applying our selectively scaled MD (or ssMD) approach to three cyclin-dependent kinase 2 (CDK2)-inhibitor complexes, we were able to significantly accelerate ligand unbinding thereby allowing, in some cases, unbinding events to occur within as little as 2 ns. Moreover, we found that we could make realistic estimates of the unbinding as well as the binding free energies (∆Gsim) of the three inhibitors from our ssMD simulation data. To accomplish this, we employed a previously described Kramers’-based rate extrapolation (KRE) method and a newly described free energy extrapolation (FEE) method. Because our ssMD approach is general, it should find utility as an easy-to-deploy, enhanced sampling method for modeling other dissociative processes.

Efficient Treatment of Fixed and Induced Dipolar Interactions

2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Lagrangian Formalism ◽  
Dipolar Interactions ◽  
Time Step ◽  
Efficient Treatment ◽  
Particle Mesh Ewald ◽  
Fixed Charges ◽  
Self Consistency ◽  
Induced Dipoles

AbstractFixed and induced point dipoles have been implemented in the Ewald and Particle-Mesh Ewald (PME) formalisms. During molecular dynamics (MD) the induced dipoles can be propagated along with the atomic positions either by interation to self-consistency at each time step, or by a Car-Parrinello (CP) technique using an extended Lagrangian formalism. The use of PME for electrostatics of fixed charges and induced dipoles together with a CP treatment of dipole propagation in MD simulations leads to a cost overhead of only 33% above that of MD simulations using standard PME with fixed charges, allowing the study of polarizability in largemacromolecular systems.

Spotting Differences in Molecular Dynamic Simulations of Influenza A M2 Protein-Ligand Complexes by Varying M2 construct, Lipid Bilayer and Force Field

2019 ◽  
Author(s):  
Dimitrios Kolokouris ◽  
Iris Kalenderoglou ◽  
Panagiotis Lagarias ◽  
Antonios Kolocouris
Keyword(s):  
Molecular Dynamic ◽  
Lipid Bilayer ◽  
Influenza A ◽  
Md Simulations ◽  
Membrane Curvature ◽  
Buffer Size ◽  
M2 Protein ◽  
Dynamic Simulations ◽  
Amphipathic Helices ◽  
Drug Protein Binding

<p>We studied by molecular dynamic (MD) simulations systems including the inward<sub>closed</sub> state of influenza A M2 protein in complex with aminoadamantane drugs in membrane bilayers. We varied the M2 construct and performed MD simulations in M2TM or M2TM with amphipathic helices (M2AH). We also varied the lipid bilayer by changing either the lipid, DMPC or POPC, POPE or POPC/cholesterol (chol), or the lipids buffer size, 10x10 Å<sup>2 </sup>or 20x20 Å<sup>2</sup>. We aimed to suggest optimal system conditions for the computational description of this ion channel and related systems. Measures performed include quantities that are available experimentally and include: (a) the position of ligand, waters and chlorine anion inside the M2 pore, (b) the passage of waters from the outward Val27 gate of M2 S31N in complex with an aminoadamantane-aryl head blocker, (c) M2 orientation, (d) the AHs conformation and structure which is affected from interactions with lipids and chol and is important for membrane curvature and virus budding. In several cases we tested OPLS2005, which is routinely applied to describe drug-protein binding, and CHARMM36 which describes reliably protein conformation. We found that for the description of the ligands position inside the M2 pore, a 10x10 Å<sup>2</sup> lipids buffer in DMPC is needed when M2TM is used but 20x20 Å<sup>2</sup> lipids buffer of the softer POPC; when M2AH is used all 10x10 Å<sup>2</sup> lipid buffers with any of the tested lipids can be used. For the passage of waters at least M2AH with a 10x10 Å<sup>2</sup> lipid buffer is needed. The folding conformation of AHs which is defined from hydrogen bonding interactions with the bilayer and the complex with chol is described well with a 10x10 Å<sup>2</sup> lipids buffer and CHARMM36. </p>

A Hydrogen Bond Between Linear Tetrapyrrole and Conserved Aspartate Causes the Far-Red Shifted Absorption of Phytochrome Photoreceptors

2020 ◽  
Author(s):  
Egle Maximowitsch ◽  
Tatiana Domratcheva
Keyword(s):  
Hydrogen Bond ◽  
Light Adaptation ◽  
Positive Charge ◽  
Pyrrole Ring ◽  
Md Simulations ◽  
Spectral Shift ◽  
Specific Domain ◽  
Study Guides ◽  
Rational Engineering ◽  
Tuning Mechanism

Photoswitching of phytochrome photoreceptors between red-absorbing (Pr) and far-red absorbing (Pfr) states triggers light adaptation of plants, bacteria and other organisms. Using quantum chemistry, we elucidate the color-tuning mechanism of phytochromes and identify the origin of the Pfr-state red-shifted spectrum. Spectral variations are explained by resonance interactions of the protonated linear tetrapyrrole chromophore. In particular, hydrogen bonding of pyrrole ring D with the strictly conserved aspartate shifts the positive charge towards ring D thereby inducing the red spectral shift. Our MD simulations demonstrate that formation of the ring D–aspartate hydrogen bond depends on interactions between the chromophore binding domain (CBD) and phytochrome specific domain (PHY). Our study guides rational engineering of fluorescent phytochromes with a far-red shifted spectrum.

Computationally Assisted Design of High Signal-to-Noise Photoinduced Electron Transfer-Based Voltage-Sensitive Dyes

2020 ◽  
Author(s):  
Rishikesh Kulkarni ◽  
Anneliese Gest ◽  
Chun Kei Lam ◽  
Benjamin Raliski ◽  
Feroz James ◽  
...  
Keyword(s):  
Electron Transfer ◽  
Dft Calculations ◽  
Photoinduced Electron Transfer ◽  
Density Functional ◽  
Embryonic Stem ◽  
High Sensitivity ◽  
Md Simulations ◽  
High Signal ◽  
Signal To Noise ◽  
Green Fluorescent

<p>High signal-to-noise optical voltage indicators will enable simultaneous interrogation of membrane potential in large ensembles of neurons. However, design principles for voltage sensors with high sensitivity and brightness remain elusive, limiting the applicability of voltage imaging. In this paper, we use molecular dynamics (MD) simulations and density functional theory (DFT) calculations to guide the design of a bright and sensitive green-fluorescent voltage-sensitive fluorophore, or VoltageFluor (VF dye), that uses photoinduced electron transfer (PeT) as a voltage-sensing mechanism. MD simulations predict an 11% increase in sensitivity due to membrane orientation, while DFT calculations predict an increase in fluorescence quantum yield, but a decrease in sensitivity due to a decrease in rate of PeT. We confirm these predictions by synthesizing a new VF dye and demonstrating that it displays the expected improvements by doubling the brightness and retaining similar sensitivity to prior VF dyes. Combining theoretical predictions and experimental validation has resulted in the synthesis of the highest signal-to-noise green VF dye to date. We use this new voltage indicator to monitor the electrophysiological maturation of human embryonic stem cell-derived medium spiny neurons. </p>

Temperature Dependence of the Air/Water Interface Revealed by Polarization Sensitive Sum-Frequency Generation Spectroscopy

2018 ◽  
Author(s):  
Daniel R. Moberg ◽  
Shelby C. Straight ◽  
Francesco Paesani
Keyword(s):  
Temperature Dependence ◽  
Low Frequency ◽  
Potential Energy Function ◽  
Md Simulations ◽  
Sum Frequency Generation ◽  
Water Molecules ◽  
Water Interface ◽  
Sum Frequency ◽  
Air Water Interface ◽  
Frequency Generation

<div> <div> <div> <p>The temperature dependence of the vibrational sum-frequency generation (vSFG) spectra of the the air/water interface is investigated using many-body molecular dynamics (MB-MD) simulations performed with the MB-pol potential energy function. The total vSFG spectra calculated for different polarization combinations are then analyzed in terms of molecular auto-correlation and cross-correlation contributions. To provide molecular-level insights into interfacial hydrogen-bonding topologies, which give rise to specific spectroscopic features, the vSFG spectra are further investigated by separating contributions associated with water molecules donating 0, 1, or 2 hydrogen bonds to neighboring water molecules. This analysis suggests that the low frequency shoulder of the free OH peak which appears at ∼3600 cm−1 is primarily due to intermolecular couplings between both singly and doubly hydrogen-bonded molecules. </p> </div> </div> </div>

Split the Charge Difference in Two! a Rule of Thumb for Adding Proper Amounts of Ions in MD Simulations

2020 ◽  
Author(s):  
Matías R. Machado ◽  
Sergio Pantano
Keyword(s):  
Molecular Dynamics ◽  
Ionic Strength ◽  
Molecular Simulations ◽  
Md Simulations ◽  
Good Practices ◽  
Rule Of Thumb ◽  
Ionic Concentrations

<p> Despite the relevance of properly setting ionic concentrations in Molecular Dynamics (MD) simulations, methods or practical rules to set ionic strength are scarce and rarely documented. Based on a recently proposed thermodynamics method we provide an accurate rule of thumb to define the electrolytic content in simulation boxes. Extending the use of good practices in setting up MD systems is promptly needed to ensure reproducibility and consistency in molecular simulations.</p>

Mechanisms of ATP to cAMP Conversion Catalyzed by the Mammalian Adenylyl Cyclase: A Role of Magnesium Coordination Shells and Proton Wires

2019 ◽  
Author(s):  
Bella Grigorenko ◽  
Igor Polyakov ◽  
Alexander Nemukhin
Keyword(s):  
Adenylyl Cyclase ◽  
Bond Cleavage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Md Simulations ◽  
Coordination Shell ◽  
Energy Profile ◽  
One Step ◽  
Type V

<p>We report a mechanism of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) conversion by the mammalian type V adenylyl cyclase revealed in molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) simulations. We characterize a set of computationally derived enzyme-substrate (ES) structures showing an important role of coordination shells of magnesium ions in the solvent accessible active site. Several stable six-fold coordination shells of Mg<sub>A</sub><sup>2+ </sup>are observed in MD simulations of ES complexes. In the lowest energy ES conformation, the coordination shell of Mg<sub>A</sub><sup>2+ </sup>does not include the O<sub>δ1</sub> atom of the conserved Asp440 residue. Starting from this conformation, a one-step reaction mechanism is characterized which includes proton transfer from the ribose O<sup>3'</sup>H<sup>3' </sup>group in ATP to Asp440 via a shuttling water molecule and P<sup>A</sup>-O<sup>3A</sup> bond cleavage and O<sup>3'</sup>-P<sup>A</sup> bond formation. The energy profile of this route is consistent with the observed reaction kinetics. In a higher energy ES conformation, Mg<sub>A</sub><sup>2+</sup> is bound to the O<sub>δ1</sub>(Asp440) atom as suggested in the relevant crystal structure of the protein with a substrate analog. The computed energy profile initiated by this ES is characterized by higher energy expenses to complete the reaction. Consistently with experimental data, we show that the Asp440Ala mutant of the enzyme should exhibit a reduced but retained activity. All considered reaction pathways include proton wires from the O<sup>3'</sup>H<sup>3' </sup>group via shuttling water molecules. </p>

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