scholarly journals Adapting free energy perturbation simulations for large macrocyclic ligands: how to dissect contributions from direct binding and free ligand flexibility

2020 ◽  
Vol 11 (8) ◽  
pp. 2269-2276 ◽  
Author(s):  
Kerstin Wallraven ◽  
Fredrik L. Holmelin ◽  
Adrian Glas ◽  
Sven Hennig ◽  
Andrey I. Frolov ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Receptor Binding ◽  
Free Ligand ◽  
Macrocyclic Ligands ◽  
Free Energy Perturbation ◽  
Direct Binding ◽  
Energy Perturbation ◽  
Dynamics Simulations

A combination of free energy perturbations and molecular dynamics simulations were applied to investigate large macrocyclic ligands and their receptor binding.

scholarly journals Insights on Small Molecule Binding to the Hv1 Proton Channel from Free Energy Calculations with Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Victoria T. Lim ◽  
Andrew D. Geragotelis ◽  
Nathan M. Lim ◽  
J. Alfredo Freites ◽  
Francesco Tombola ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Free Energy Calculations ◽  
Proton Channel ◽  
Channel Blockers ◽  
Main Function ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Effective Channel

Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we compute relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We use alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model, sheds light on the preferred tautomeric state of the blocker that binds Hv1, and lays the groundwork for future studies on adapting the blocker molecule for more effective channel blocking.

scholarly journals Effect of mutations on binding of ligands to guanine riboswitch probed by free energy perturbation and molecular dynamics simulations

2019 ◽  
Vol 47 (13) ◽  
pp. 6618-6631 ◽  
Author(s):  
Jianzhong Chen ◽  
Xingyu Wang ◽  
Laixue Pang ◽  
John Z H Zhang ◽  
Tong Zhu
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Drug Targets ◽  
Md Simulations ◽  
Free Energy Perturbation ◽  
Potential Drug ◽  
Free Energy Decomposition ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Potential Drug Targets

Abstract Riboswitches can regulate gene expression by direct and specific interactions with ligands and have recently attracted interest as potential drug targets for antibacterial. In this work, molecular dynamics (MD) simulations, free energy perturbation (FEP) and molecular mechanics generalized Born surface area (MM-GBSA) methods were integrated to probe the effect of mutations on the binding of ligands to guanine riboswitch (GR). The results not only show that binding free energies predicted by FEP and MM-GBSA obtain an excellent correlation, but also indicate that mutations involved in the current study can strengthen the binding affinity of ligands GR. Residue-based free energy decomposition was applied to compute ligand-nucleotide interactions and the results suggest that mutations highly affect interactions of ligands with key nucleotides U22, U51 and C74. Dynamics analyses based on MD trajectories indicate that mutations not only regulate the structural flexibility but also change the internal motion modes of GR, especially for the structures J12, J23 and J31, which implies that the aptamer domain activity of GR is extremely plastic and thus readily tunable by nucleotide mutations. This study is expected to provide useful molecular basis and dynamics information for the understanding of the function of GR and possibility as potential drug targets for antibacterial.

scholarly journals Solvation Free Energy of Protonated Lysine: Molecular Dynamics Study

2021 ◽  
Vol 7 (2) ◽  
pp. 69-75
Author(s):  
S. P. Khanal ◽  
B. Poudel ◽  
R. P. Koirala ◽  
N. P. Adhikari
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Energy Difference ◽  
Solvation Free Energy ◽  
Free Energy Perturbation ◽  
Free Energy Difference ◽  
Free Energy Of Solvation ◽  
Acceptance Ratio ◽  
Energy Perturbation ◽  
Dynamics Simulations

In the present work, we have used an alchemical approach for calculating solvation free energy of protonated lysine in water from molecular dynamics simulations. These approaches use a non-physical pathway between two end states in order to compute free energy difference from the set of simulations. The solute is modeled using bonded and non-bonded interactions described by OPLS-AA potential, while four different water models: TIP3P, SPC, SPC/E and TIP4P are used. The free energy of solvation of protonated lysine in water has been estimated using thermodynamic integration, free energy perturbation, and Bennett acceptance ratio methods at 310 K temperature. The contributions to the free energy due to van der Waals and electrostatics parameters are also separately computed. The estimated values of free energy of solvation using different methods are in well agreement with previously reported experimental value within 14 %.

scholarly journals Insights on Small Molecule Binding to the Hv1 Proton Channel from Free Energy Calculations with Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Victoria T. Lim ◽  
Andrew D. Geragotelis ◽  
Nathan M. Lim ◽  
J. Alfredo Freites ◽  
Francesco Tombola ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Free Energy Calculations ◽  
Proton Channel ◽  
Channel Blockers ◽  
Main Function ◽  
Energy Perturbation ◽  
Dynamics Simulations ◽  
Effective Channel

Hv1 is a voltage-gated proton channel whose main function is to facilitate extrusion of protons from the cell. The development of effective channel blockers for Hv1 can lead to new therapeutics for the treatment of maladies related to Hv1 dysfunction. Although the mechanism of proton permeation in Hv1 remains to be elucidated, a series of small molecules have been discovered to inhibit Hv1. Here, we compute relative binding free energies of a prototypical Hv1 blocker on a model of human Hv1 in an open state. We use alchemical free energy perturbation techniques based on atomistic molecular dynamics simulations. The results support our proposed open state model, sheds light on the preferred tautomeric state of the blocker that binds Hv1, and lays the groundwork for future studies on adapting the blocker molecule for more effective channel blocking.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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