A molecular dynamics study on liquid 1-octanol. Part 3. Evaluating octanol/water partition coefficients of novel thrombin inhibitors via free-energy perturbations

2005 ◽  
Vol 102 (5) ◽  
pp. 542-553 ◽  
Author(s):  
César Augusto Fernandes De Oliveira ◽  
Cristiano Ruch Werneck Guimarães ◽  
Heloisa De Mello ◽  
Aurea Echevarria ◽  
Ricardo Bicca De Alencastro
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Partition Coefficients ◽  
Thrombin Inhibitors ◽  
Free Energy Perturbations

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

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>

scholarly journals Evaluation of log P, pKa, and log D predictions from the SAMPL7 blind challenge

2021 ◽  
Author(s):  
Teresa Danielle Bergazin ◽  
Nicolas Tielker ◽  
Yingying Zhang ◽  
Junjun Mao ◽  
M. R. Gunner ◽  
...  
Keyword(s):  
Free Energy ◽  
Partition Coefficients ◽  
Physical Property ◽  
Rational Drug Design ◽  
Log P ◽  
Prediction Methods ◽  
Research Groups ◽  
Reasonable Accuracy ◽  
Statistical Assessment ◽  
Rational Drug

AbstractThe Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges focuses the computational modeling community on areas in need of improvement for rational drug design. The SAMPL7 physical property challenge dealt with prediction of octanol-water partition coefficients and pKa for 22 compounds. The dataset was composed of a series of N-acylsulfonamides and related bioisosteres. 17 research groups participated in the log P challenge, submitting 33 blind submissions total. For the pKa challenge, 7 different groups participated, submitting 9 blind submissions in total. Overall, the accuracy of octanol-water log P predictions in the SAMPL7 challenge was lower than octanol-water log P predictions in SAMPL6, likely due to a more diverse dataset. Compared to the SAMPL6 pKa challenge, accuracy remains unchanged in SAMPL7. Interestingly, here, though macroscopic pKa values were often predicted with reasonable accuracy, there was dramatically more disagreement among participants as to which microscopic transitions produced these values (with methods often disagreeing even as to the sign of the free energy change associated with certain transitions), indicating far more work needs to be done on pKa prediction methods.

scholarly journals Binding free energy predictions in host-guest systems using Autodock4. A retrospective analysis on SAMPL6, SAMPL7 and SAMPL8 challenges

2021 ◽  
Author(s):  
Lorenzo Casbarra ◽  
Piero Procacci
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Drug Discovery ◽  
Binding Free Energy ◽  
Cost Ratio ◽  
Benefit Cost Ratio ◽  
Docking Program ◽  
Benefit Cost ◽  
Overall Reliability ◽  
Absolute Binding Free Energy

AbstractWe systematically tested the Autodock4 docking program for absolute binding free energy predictions using the host-guest systems from the recent SAMPL6, SAMPL7 and SAMPL8 challenges. We found that Autodock4 behaves surprisingly well, outperforming in many instances expensive molecular dynamics or quantum chemistry techniques, with an extremely favorable benefit-cost ratio. Some interesting features of Autodock4 predictions are revealed, yielding valuable hints on the overall reliability of docking screening campaigns in drug discovery projects.

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