scholarly journals Adaptive free energy sampling in multidimensional collective variable space using boxed molecular dynamics

2016 ◽  
Vol 195 ◽  
pp. 395-419 ◽  
Author(s):  
Mike O'Connor ◽  
Emanuele Paci ◽  
Simon McIntosh-Smith ◽  
David R. Glowacki
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Rare Event ◽  
Potential Of Mean Force ◽  
Good Evidence ◽  
Collective Variable ◽  
Rigid Body Dynamics ◽  
Free Energy Surface ◽  
Molecular Configuration ◽  
Free Energy Sampling

The past decade has seen the development of a new class of rare event methods in which molecular configuration space is divided into a set of boundaries/interfaces, and then short trajectories are run between boundaries. For all these methods, an important concern is how to generate boundaries. In this paper, we outline an algorithm for adaptively generating boundaries along a free energy surface in multi-dimensional collective variable (CV) space, building on the boxed molecular dynamics (BXD) rare event algorithm. BXD is a simple technique for accelerating the simulation of rare events and free energy sampling which has proven useful for calculating kinetics and free energy profiles in reactive and non-reactive molecular dynamics (MD) simulations across a range of systems, in both NVT and NVE ensembles. Two key developments outlined in this paper make it possible to automate BXD, and to adaptively map free energy and kinetics in complex systems. First, we have generalized BXD to multidimensional CV space. Using strategies from rigid-body dynamics, we have derived a simple and general velocity-reflection procedure that conserves energy for arbitrary collective variable definitions in multiple dimensions, and show that it is straightforward to apply BXD to sampling in multidimensional CV space so long as the Cartesian gradients ∇CV are available. Second, we have modified BXD to undertake on-the-fly statistical analysis during a trajectory, harnessing the information content latent in the dynamics to automatically determine boundary locations. Such automation not only makes BXD considerably easier to use; it also guarantees optimal boundaries, speeding up convergence. We have tested the multidimensional adaptive BXD procedure by calculating the potential of mean force for a chemical reaction recently investigated using both experimental and computational approaches – i.e., F + CD3CN → DF + D2CN in both the gas phase and a strongly coupled explicit CD3CN solvent. The results obtained using multidimensional adaptive BXD agree well with previously published experimental and computational results, providing good evidence for its reliability.

scholarly journals Multiscale Simulation Reveals Passive Proton Transport Through SERCA on the Microsecond Timescale

2020 ◽  
Author(s):  
Chenghan Li ◽  
Zhi Yue ◽  
L. Michel Espinoza-Fonseca ◽  
Gregory A. Voth
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Sarcoplasmic Reticulum ◽  
Binding Site ◽  
Proton Transport ◽  
Computational Study ◽  
Multiscale Simulation ◽  
Proton Pumping ◽  
Reactive Molecular Dynamics ◽  
Free Energy Sampling

ABSTRACTThe sarcoplasmic reticulum Ca2+-ATPase (SERCA) transports two Ca2+ ions from the cytoplasm to the reticulum lumen at the expense of ATP hydrolysis. In addition to transporting Ca2+, SERCA facilitates bidirectional proton transport across the sarcoplasmic reticulum to maintain the charge balance of the transport sites and to balance the charge deficit generated by the exchange of Ca2+. Previous studies have shown the existence of a transient water-filled pore in SERCA that connects the Ca2+-binding sites with the lumen, but the capacity of this pathway to sustain passive proton transport has remained unknown. In this study, we used the multiscale reactive molecular dynamics (MS-RMD) method and free energy sampling to quantify the free energy profile and timescale of the proton transport across this pathway while also explicitly accounting for the dynamically coupled hydration changes of the pore. We find that proton transport from the central binding site to the lumen has a microsecond timescale, revealing a novel passive cytoplasm-to-lumen proton flow beside the well-known inverse proton countertransport occurring in active Ca2+ transport. We propose that this proton transport mechanism is operational and serves as a functional conduit for passive proton transport across the sarcoplasmic reticulum.SIGNIFICANCEMultiscale reactive molecular dynamics combined with free energy sampling was applied to study proton transport through a transient water pore connecting the Ca2+-binding site to the lumen in SERCA. This is the first computational study of this large biomolecular system that treats the hydrated excess proton and its transport through water structures and amino acids explicitly. When also correctly accounting for the hydration fluctuations of the pore, it is found that a transiently hydrated channel can transport protons on a microsecond timescale. These results quantitatively support the hypothesis of the proton intake into the sarcoplasm via SERCA, in addition to the well-known proton pumping by SERCA to the cytoplasm along with Ca2+ transport.

MOLECULAR SIMULATION OF α-TOCOPHEROL PASSING ACROSS DPPC LIPID USING POTENTIAL OF MEAN FORCE AND ACCELERATED MOLECULAR DYNAMICS METHOD

2013 ◽  
Vol 12 (08) ◽  
pp. 1341011 ◽  
Author(s):  
FANCUI MENG
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Computation Time ◽  
Potential Of Mean Force ◽  
Accelerated Molecular Dynamics ◽  
Energy Profiles ◽  
Lipid System ◽  
Dynamics Method ◽  
Free Energy Profiles

In this paper the process of α-tocopherol (TCP) passing across DPPC membrane was simulated using both the potential of mean force (PMF) and the accelerated molecular dynamics (aMD) methods, respectively. Energy properties, hydrogen bonds and orientation have been compared between these two methods and several conclusions have been obtained. The results indicate that TCP tends to stay at z = 1.2 nm of lipid bilayer. The binding free energy profiles of these two methods are alike. All these show that aMD could obtain comparable results as PMF method, while needs less computation time and resources. Therefore, aMD method could be used as an alternative method for prediction of transport properties of drug-lipid system.

scholarly journals Thermodynamic and Kinetic Characterization of Protein Conformational Dynamics within a Riemannian Framework

2021 ◽  
Author(s):  
Curtis Goolsby ◽  
Ashkan Fakharzadeh ◽  
Mahmoud Moradi
Keyword(s):  
Free Energy ◽  
Transition Rate ◽  
Conformational Dynamics ◽  
Diffusion Constant ◽  
Minimum Free Energy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Collective Variable ◽  
Bayesian Estimator ◽  
Riemannian Framework

AbstractWe have formulated a Riemannian framework for describing the geometry of collective variable spaces of biomolecules within the context of molecular dynamics (MD) simulations. The formalism provides a theoretical framework to develop enhanced sampling techniques, path-finding algorithms, and transition rate estimators consistent with a Riemannian treatment of the collective variable space, where the quantities of interest such as the potential of mean force (PMF) and minimum free energy path (MFEP) remain invariant under coordinate transformation. Specific algorithms within this framework are discussed such as the Riemannian umbrella sampling, the Riemannian string method, and a Riemannian-Bayesian estimator of free energy and diffusion constant, which can be used to estimate the transition rate along an MFEP.

scholarly journals Combining Well-Tempered Metadynamics Simulation and SPR Assays to Characterize the Binding Mechanism of the Universal T-Lymphocyte Tetanus Toxin Epitope TT830-843

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Artur A. M. L. Brandt ◽  
Rodrigo N. Rodrigues-da-Silva ◽  
Josué C. Lima-Junior ◽  
Carlos R. Alves ◽  
Franklin de Souza-Silva
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
T Cell ◽  
T Cell Activation ◽  
Tetanus Toxin ◽  
Cell Activation ◽  
Cell Epitope ◽  
In Vitro Assays ◽  
Stable Complex ◽  
Free Energy Surface

Peptide TT830-843 from the tetanus toxin is a universal T-cell epitope. It helps in vaccination and induces T-cell activation. However, the fine molecular interaction between this antigen and the major histocompatibility complex (MHC) remains unknown. Molecular analysis of its interaction with murine MHC (H-2) was proposed to explore its immune response efficiency. Molecular dynamics simulations are important mechanisms for understanding the basis of protein-ligand interactions, and metadynamics is a useful technique for enhancing sampling in molecular dynamics. SPR (surface plasmon resonance) assays were used to validate whether the metadynamics results are in accordance with the experimental results. The peptide TT830-843 unbinding process was simulated, and the free energy surface reconstruction revealed a detailed conformational landscape. The simulation described the exiting path as a stepwise mechanism between progressive detachment states. We pointed out how the terminus regions act as anchors for binding and how the detachment mechanism includes the opening of α-helices to permit the peptide’s central region dissociation. The results indicated the peptide/H-2 receptor encounter occurs within a distance lesser than 27.5 Å, and the encounter can evolve to form a stable complex. SPR assays confirmed the complex peptide/H-2 as a thermodynamically stable system, exhibiting enough free energy to interact with TCR on the antigen-presenting cell surface. Therefore, combining in silico and in vitro assays provided significant evidence to support the peptide/H-2 complex formation.

scholarly journals Exploring the free energy surface using ab initio molecular dynamics

2016 ◽  
Vol 144 (16) ◽  
pp. 164101 ◽  
Author(s):  
Amit Samanta ◽  
Miguel A. Morales ◽  
Eric Schwegler
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio ◽  
Energy Surface ◽  
Ab Initio Molecular Dynamics ◽  
Free Energy Surface

scholarly journals Synergistic Effect of Chemical Penetration Enhancers on Lidocaine Permeability Revealed by Coarse-Grained Molecular Dynamics Simulations

Membranes ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 410
Author(s):  
Marine E. Bozdaganyan ◽  
Philipp S. Orekhov
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Synergistic Effect ◽  
Potential Of Mean Force ◽  
Penetration Enhancers ◽  
Coarse Grained ◽  
Membrane Thickness ◽  
Free Energy Barrier ◽  
Small Molecular Weight ◽  
Chemical Penetration Enhancers

The search for new formulations for transdermal drug delivery (TDD) is an important field in medicine and cosmetology. Molecules with specific physicochemical properties which can increase the permeability of active ingredients across the stratum corneum (SC) are called chemical penetration enhancers (CPEs), and it was shown that some CPEs can act synergistically. In this study, we performed coarse-grained (CG) molecular dynamics (MD) simulations of the lidocaine delivery facilitated by two CPEs—linoleic acid (LA) and ethanol—through the SC model membrane containing cholesterol, N-Stearoylsphingosine (DCPE), and behenic acid. In our simulations, we probed the effects of individual CPEs as well as their combination on various properties of the SC membrane and the lidocaine penetration across it. We demonstrated that the addition of both CPEs decreases the membrane thickness and the order parameters of the DPCE hydrocarbon chains. Moreover, LA also enhances diffusion of the SC membrane components, especially cholesterol. The estimated potential of mean force (PMF) profiles for the lidocaine translocation across SC in the presence/absence of two individual CPEs and their combination demonstrated that while ethanol lowers the free energy barrier for lidocaine to enter SC, LA decreases the depth of the free energy minima for lidocaine inside SC. These two effects supposedly result in synergistic penetration enhancement of drugs. Altogether, the present simulations provide a detailed molecular picture of CPEs’ action and their synergistic effect on the penetration of small molecular weight therapeutics that can be beneficial for the design of novel drug and cosmetics formulations.

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