scholarly journals Mechanistic Analysis of Light-Driven Overcrowded Alkene-Based Molecular Motors by Multiscale Molecular Simulations

2020 ◽  
Author(s):  
Mudong Feng ◽  
Michael K. Gilson
Keyword(s):  
Molecular Motors ◽  
Performance Metrics ◽  
Multiple Scales ◽  
Mechanical Energy ◽  
Md Simulations ◽  
Maximal Power Output ◽  
Conformational Substates ◽  
Rotation Rates ◽  
Full Rotation ◽  
Energy Surfaces

We analyze light-driven overcrowded alkene-based molecular motors, an intriguing class of small molecules that have the potential to generate MHz-scale rotation rates. The full rotation process is simulated at multiple scales by combining quantum surface-hopping molecular dynamics (MD) simulations for the photoisomerization step with classical MD simulations for the thermal helix inversion step. A Markov state analysis resolves conformational substates, their interconversion kinetics, and their roles in the motor’s rotation process. Furthermore, motor performance metrics, including rotation rate and maximal power output, are computed to validate computations against experimental measurements and to inform future designs. Lastly, we find that to correctly model these motors, the force field must be optimized by fitting selected parameters to reference quantum mechanical energy surfaces. Overall, our simulations yield encouraging agreement with experimental observables such as rotation rates, and provide mechanistic insights that may help future designs.

scholarly journals Mechanistic Analysis of Light-Driven Overcrowded Alkene-Based Molecular Motors by Multiscale Molecular Simulations

2020 ◽  
Author(s):  
Mudong Feng ◽  
Michael K. Gilson
Keyword(s):  
Molecular Motors ◽  
Performance Metrics ◽  
Multiple Scales ◽  
Mechanical Energy ◽  
Md Simulations ◽  
Maximal Power Output ◽  
Conformational Substates ◽  
Rotation Rates ◽  
Full Rotation ◽  
Energy Surfaces

We analyze light-driven overcrowded alkene-based molecular motors, an intriguing class of small molecules that have the potential to generate MHz-scale rotation rates. The full rotation process is simulated at multiple scales by combining quantum surface-hopping molecular dynamics (MD) simulations for the photoisomerization step with classical MD simulations for the thermal helix inversion step. A Markov state analysis resolves conformational substates, their interconversion kinetics, and their roles in the motor’s rotation process. Furthermore, motor performance metrics, including rotation rate and maximal power output, are computed to validate computations against experimental measurements and to inform future designs. Lastly, we find that to correctly model these motors, the force field must be optimized by fitting selected parameters to reference quantum mechanical energy surfaces. Overall, our simulations yield encouraging agreement with experimental observables such as rotation rates, and provide mechanistic insights that may help future designs.

Testing and Optimizing the Drude Polarizable Force Field for Blocked Amino Acids Based on High-Level Quantum-Mechanical Energy Surfaces

2022 ◽  
pp. 1-9
Author(s):  
Jinfeng Chen ◽  
Gerhard König
Keyword(s):  
Amino Acids ◽  
Force Field ◽  
Energy Surface ◽  
Mechanical Energy ◽  
Quantum Mechanical ◽  
Polarizable Force Field ◽  
Conformational Substates ◽  
Reorganization Energies ◽  
High Level ◽  
Energy Surfaces

The correct reproduction of conformational substates of amino acids was tested for the CHARMM Drude polarizable force field. This was achieved by evaluating the reorganization energies for all low lying energy minima occurring in all 15 neutral blocked amino acids on a quantum-mechanical (QM) energy surface at the MP2/cc-pVDZ level. The results indicate that the bonded parameters of the N-acetyl (ACE) and N-Methylamide (CT3) blocking groups lead to significant discrepancies. A reparametrization of five bond angles significantly improved the agreement with the QM energy surface. The corrected Drude force field exhibits almost the same average reorganization energies relative to the MP2 energy surface as the AM1 and PM3 semi-empirical methods.

scholarly journals Motor-Like Properties of Non-Motor Enzymes

2017 ◽  
Author(s):  
David R. Slochower ◽  
Michael K. Gilson
Keyword(s):  
Molecular Motors ◽  
Adenosine Kinase ◽  
Chiral Molecules ◽  
Collective Variables ◽  
Rotation Rates ◽  
Motor Enzymes ◽  
Directional Motion ◽  
Power Outputs ◽  
Dynamics Simulations ◽  
Energy Surfaces

AbstractMolecular motors are thought to generate force and directional motion via nonequilibrium switching between energy surfaces. Because all enzymes can undergo such switching, we hypothesized that the ability to generate rotary motion and torque is not unique to highly adapted biological motor proteins, but is instead a common feature of enzymes. We used molecular dynamics simulations to compute energy surfaces for hundreds of torsions in three enzymes, adenosine kinase, protein kinase A, and HIV-1 protease, and used these energy surfaces within a kinetic model that accounts for intersurface switching and intrasurface probability flows. When substrate is out of equilibrium with product, we find computed torsion rotation rates up ~140 cycle s-1, with stall torques up to ~2 kcal mol-1 cycle-1, and power outputs up to ~50 kcal mol-1 s-1. We argue that these enzymes are instances of a general phenomenon of directional probability flows on asymmetric energy surfaces for systems out of equilibrium. Thus, we conjecture that cyclic probability fluxes, corresponding to rotations of torsions and higher-order collective variables, exist in any chiral molecule driven between states in a non-equilibrium manner; we call this the Asymmetry-Directionality conjecture. This is expected to apply as well to synthetic chiral molecules switched in a nonequilibrium manner between energy surfaces by light, redox chemistry, or catalysis.

scholarly journals The Cross-Bridge Spring: Can Cool Muscles Store Elastic Energy?

Science ◽  
2013 ◽  
Vol 340 (6137) ◽  
pp. 1217-1220 ◽  
Author(s):  
N. T. George ◽  
T. C. Irving ◽  
C. D. Williams ◽  
T. L. Daniel
Keyword(s):  
Energy Storage ◽  
Elastic Energy ◽  
Molecular Motors ◽  
High Speed ◽  
Mechanical Energy ◽  
Elastic Strain Energy ◽  
Time Resolved ◽  
X Ray ◽  
Cross Bridge ◽  
Cross Bridges

Muscles not only generate force. They may act as springs, providing energy storage to drive locomotion. Although extensible myofilaments are implicated as sites of energy storage, we show that intramuscular temperature gradients may enable molecular motors (cross-bridges) to store elastic strain energy. By using time-resolved small-angle x-ray diffraction paired with in situ measurements of mechanical energy exchange in flight muscles of Manduca sexta, we produced high-speed movies of x-ray equatorial reflections, indicating cross-bridge association with myofilaments. A temperature gradient within the flight muscle leads to lower cross-bridge cycling in the cooler regions. Those cross-bridges could elastically return energy at the extrema of muscle lengthening and shortening, helping drive cyclic wing motions. These results suggest that cross-bridges can perform functions other than contraction, acting as molecular links for elastic energy storage.

scholarly journals Elucidating the Molecular Basis of pH Activation of an Engineered Mechanosensitive Channel

2019 ◽  
Author(s):  
Kalyan Immadisetty ◽  
Adithya Polasa ◽  
Reid Shelton ◽  
Mahmoud Moradi
Keyword(s):  
Mechanical Energy ◽  
Salt Bridge ◽  
Md Simulations ◽  
Pressure Profile ◽  
Chemical Signals ◽  
Activation Mechanism ◽  
Activation Process ◽  
Ph Change ◽  
Non Equilibrium Molecular Dynamics ◽  
First Time

AbstractMechanosensitive (MS) channels detect and respond to changes in the pressure profile of cellular membranes and transduce the mechanical energy into electrical and/or chemical signals. By re-engineering, however, the activation of some MS channels can be triggered by chemical signals such as pH change. Here, for the first time, we have elucidated, at an atomic level, the activation mechanism of an engineered MscL channel in response to the pH changes of the environment through a combination of equilibrium and non-equilibrium molecular dynamics (MD) simulations. The key highlights of our proposed activation mechanism are that: (1) periplasmic loops play a key role in activation, (2) loss of various hydrogen bonding and salt bridge interactions in the engineered MscL channel causes the opening of the channel, and (3) the most significant interactions lost during the activation process are those between the transmembrane (TM) helices 1 and 2 (TM1 and TM2). The orientation-based method in this work for generating and optimizing an open model of engineered MscL is a promising method for generating unknown states of proteins and for studying the activation processes in ion channels. This work facilitates the studies aimed at designing pH-triggered drug delivery liposomes (DDL), which embed MscL as a nanovalve.

scholarly journals Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

2020 ◽  
Author(s):  
Shae-Lynn Lahey ◽  
Từ Nguyễn Thiên Phúc ◽  
Christopher Rowley
Keyword(s):  
Neural Network ◽  
Potential Energy ◽  
Force Field ◽  
Potential Energy Surfaces ◽  
Md Simulations ◽  
Absolute Deviation ◽  
Torsional Potential ◽  
The Mean ◽  
High Level ◽  
Energy Surfaces

Many drug molecules contain biaryl fragments, resulting in a torsional barrier corresponding to rotation around the bond linking the aryls. The potential energy surfaces of these torsions vary significantly due to steric and electronic effects, ultimately affecting the relative stability of the molecular conformations in the protein-bound and solution states. Simulations of protein--ligand binding require accurate computational models to represent the intramolecular interactions to provide accurate predictions of the structure and dynamics of binding. In this paper, we compare four force fields (Generalized AMBER Force Field (GAFF), Open Force Field (OpenFF), CHARMM General Force Field (CGenFF), Optimized Potentials for Liquid Simulations (OPLS)) and two neural network potentials (ANI-2x, ANI-1ccx) in their ability to predict the torsional potential energy surfaces of 88 biaryls extracted from drug fragments. The mean of the absolute deviation over the full PES (MADF) and the mean absolute deviation of the torsion rotational barrier height (MADB) relative to high-level ab initio reference data was used as a measure of accuracy. In comparison to high-level ab-initio data, ANI-1ccx was most accurate for predicting the barrier height (MADF: 0.5~kcal/mol, MADB:~0.8~kcal/mol), followed closely by ANI-2x (MADF: 0.5~kcal/mol, MADB:~1.0~kcal/mol), then CGenFF (MADF: 0.8~kcal/mol, MADB: 1.3~kcal/mol), OpenFF (MADF: 1.5~kcal/mol, MADB: 1.4~kcal/mol), GAFF (MADF: 1.2~kcal/mol, MADB: 2.6~kcal/mol), and finally OPLS (MADF: 1.5~kcal/mol, MADB: 2.8~kcal/mol). Significantly, the NNPs are systematically more accurate and more reliable than any of the force fields. As a practical example, the neural network potential/molecular mechanics (NNP/MM) method was used to simulate the isomerization of ozanimod, a drug used for multiple sclerosis. Multi-nanosecond molecular dynamics (MD) simulations in an explicit aqueous solvent were performed, as well as umbrella sampling and adaptive biasing force enhanced sampling techniques. These theories predicted a rate of isomerization of $4.30 \times 10^{-1}$ ns$^{-1}$, which is consistent with direct MD simulations.

scholarly journals The Gantry as a Drive for a Horizontal Bike: Initial Investigation of Rotary Work

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Łukasz Bereś ◽  
Paweł Pyrzanowski
Keyword(s):  
Mathematical Analysis ◽  
Rotational Motion ◽  
Mechanical Energy ◽  
Gear Wheel ◽  
Static Tests ◽  
Initial Investigation ◽  
Full Rotation ◽  
Drive Systems ◽  
To Receive

The gantry drive (also, “the gantry”) is a mechanism that receives human-generated mechanical energy. The gantry used in a horizontal bike is a type of drive, and it is an alternative to a typical crankset. The purpose of this paper was to compare rotary work generated by the gantry and the crankset. The comparative criterion for the gantry and the crankset was work in rotational motion. The comparison was based on static tests; forces put into both drive systems were measured, and the rotary work was mathematically calculated. The forces put into the drive systems were measured for a man 177 cm tall and of 76 kg mass. To facilitate analysis and tests, the first gear wheel to receive force from the toothed rack (the gantry drive) was assumed to have the same radius as the crank (the crankset drive). Mathematical analysis performed for one full rotation (360°) of the first gear wheel and crankset showed that rotary work for the gantry was 2117.31 J and for the crankset 804.81 J. Ultimately, it was shown that the gantry can better receive mechanical energy from the human than the crankset. This means that a human will be less tired when riding a horizontal bike equipped with the gantry compared to a horizontal bike equipped with the crankset; assuming that in both cases, the bike speed is the same. Additionally, thanks to the use of the gantry drive in a horizontal bike, it is possible to achieve higher speeds compared to a horizontal bike equipped with the crankset.

scholarly journals Quantum-Classical Simulation of Molecular Motors Driven Only by Light

2021 ◽  
Author(s):  
Atreya Majumdar ◽  
Thomas L.C. Jansen
Keyword(s):  
Molecular Motors ◽  
State Energy ◽  
Molecular System ◽  
Electronic Coupling ◽  
Excited State Energy ◽  
Thermally Activated ◽  
Rate Determining Step ◽  
Classical Simulation ◽  
Full Rotation ◽  
Working Principle

<div><div><div><p>Molecular motors that exhibit controlled unidirectional rotation provide great prospects for many types of applications including nanorobotics. Existing rotational motors have two key components: photoisomerisation around a pi-bond followed by a thermally activated helical inversion; the latter being the rate-determining step. We propose an alternative molecular system, where the rotation is caused by the electronic coupling<br>of chromophores. This is used to engineer the excited state energy surface and achieve unidirectional rotation using light as the only input and avoid the slow thermal step, potentially leading to much faster operational speeds. To test the working principle we employ quantum-classical calculations to study the dynamics of such a system. We estimate that motors build on this principle should be able to work on a sub-nanosecond timescale for such a full rotation. We explore the parameter space of our model to guide the design of a molecule which can act as such motor.</p></div></div></div>

Benchmarking Force Field and the ANI Neural Network Potentials for the Torsional Potential Energy Surface of Biaryl Drug Fragments

2020 ◽  
Author(s):  
Shae-Lynn Lahey ◽  
Từ Nguyễn Thiên Phúc ◽  
Christopher Rowley
Keyword(s):  
Neural Network ◽  
Potential Energy ◽  
Force Field ◽  
Potential Energy Surfaces ◽  
Md Simulations ◽  
Absolute Deviation ◽  
Torsional Potential ◽  
The Mean ◽  
High Level ◽  
Energy Surfaces

Many drug molecules contain biaryl fragments, resulting in a torsional barrier corresponding to rotation around the bond linking the aryls. The potential energy surfaces of these torsions vary significantly due to steric and electronic effects, ultimately affecting the relative stability of the molecular conformations in the protein-bound and solution states. Simulations of protein--ligand binding require accurate computational models to represent the intramolecular interactions to provide accurate predictions of the structure and dynamics of binding. In this paper, we compare four force fields (Generalized AMBER Force Field (GAFF), Open Force Field (OpenFF), CHARMM General Force Field (CGenFF), Optimized Potentials for Liquid Simulations (OPLS)) and two neural network potentials (ANI-2x, ANI-1ccx) in their ability to predict the torsional potential energy surfaces of 88 biaryls extracted from drug fragments. The mean of the absolute deviation over the full PES (MADF) and the mean absolute deviation of the torsion rotational barrier height (MADB) relative to high-level ab initio reference data was used as a measure of accuracy. In comparison to high-level ab-initio data, ANI-1ccx was most accurate for predicting the barrier height (MADF: 0.5~kcal/mol, MADB:~0.8~kcal/mol), followed closely by ANI-2x (MADF: 0.5~kcal/mol, MADB:~1.0~kcal/mol), then CGenFF (MADF: 0.8~kcal/mol, MADB: 1.3~kcal/mol), OpenFF (MADF: 1.5~kcal/mol, MADB: 1.4~kcal/mol), GAFF (MADF: 1.2~kcal/mol, MADB: 2.6~kcal/mol), and finally OPLS (MADF: 1.5~kcal/mol, MADB: 2.8~kcal/mol). Significantly, the NNPs are systematically more accurate and more reliable than any of the force fields. As a practical example, the neural network potential/molecular mechanics (NNP/MM) method was used to simulate the isomerization of ozanimod, a drug used for multiple sclerosis. Multi-nanosecond molecular dynamics (MD) simulations in an explicit aqueous solvent were performed, as well as umbrella sampling and adaptive biasing force enhanced sampling techniques. These theories predicted a rate of isomerization of $4.30 \times 10^{-1}$ ns$^{-1}$, which is consistent with direct MD simulations.

scholarly journals A chemo-mechanical free-energy-based approach to model durotaxis and extracellular stiffness-dependent contraction and polarization of cells

2016 ◽  
Vol 6 (1) ◽  
pp. 20150067 ◽  
Author(s):  
Vivek B. Shenoy ◽  
Hailong Wang ◽  
Xiao Wang
Keyword(s):  
Free Energy ◽  
Molecular Motors ◽  
Mechanical Energy ◽  
Second Law Of Thermodynamics ◽  
Mechanical Coupling ◽  
Coupling Parameters ◽  
Chemical Free Energy ◽  
Myosin Motors ◽  
Stress Dependent ◽  
Extracellular Environment

We propose a chemo-mechanical model based on stress-dependent recruitment of myosin motors to describe how the contractility, polarization and strain in cells vary with the stiffness of their surroundings and their shape. A contractility tensor, which depends on the distribution of myosin motors, is introduced to describe the chemical free energy of the cell due to myosin recruitment. We explicitly include the contributions to the free energy that arise from mechanosensitive signalling pathways (such as the SFX, Rho-Rock and MLCK pathways) through chemo-mechanical coupling parameters. Taking the variations of the total free energy, which consists of the chemical and mechanical components, in accordance with the second law of thermodynamics provides equations for the temporal evolution of the active stress and the contractility tensor. Following this approach, we are able to recover the well-known Hill relation for active stresses, based on the fundamental principles of irreversible thermodynamics rather than phenomenology. We have numerically implemented our free energy-based approach to model spatial distribution of strain and contractility in (i) cells supported by flexible microposts, (ii) cells on two-dimensional substrates, and (iii) cells in three-dimensional matrices. We demonstrate how the polarization of the cells and the orientation of stress fibres can be deduced from the eigenvalues and eigenvectors of the contractility tensor. Our calculations suggest that the chemical free energy of the cell decreases with the stiffness of the extracellular environment as the cytoskeleton polarizes in response to stress-dependent recruitment of molecular motors. The mechanical energy, which includes the strain energy and motor potential energy, however, increases with stiffness, but the overall energy is lower for cells in stiffer environments. This provides a thermodynamic basis for durotaxis, whereby cells preferentially migrate towards stiffer regions of the extracellular environment. Our models also explain, from an energetic perspective, why the shape of the cells can change in response to stiffness of the surroundings. The effect of the stiffness of the nucleus on its shape and the orientation of the stress fibres is also studied for all the above geometries. Along with making testable predictions, we have estimated the magnitudes of the chemo-mechanical coupling parameters for myofibroblasts based on data reported in the literature.

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