scholarly journals Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation

2017 ◽  
Author(s):  
Wanli You ◽  
Zhiye Tang ◽  
Chia-en A. Chang
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Conformational Changes ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Conformational Space ◽  
Drug Candidate ◽  
Energy Calculation ◽  
Dissociation Pathway ◽  
Collective Variables

AbstractThe kinetics of ligand dissociation has been found to be crucial for a good drug candidate. Therefore, examining the underlying free energy profile of the dissociation that governs the kinetics becomes important. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems. The potential of mean force (PMF) computed from US seems to always produce binding affinity and energy barriers that more or less agree with experiments. However, such PMFs are influenced by many practical aspects, like the method used to generate the initial dissociation pathway, collective variables (CVs) that used to describe the reaction coordinate (RC), and how intensive the sampling is in the conformational space restrained by the CVs. These critical factors were rarely studied. Here we applied US to study the dissociation processes of β-cyclodextrin (β-CD) and p38α complex systems. For β-CD, we used three different β-CD conformations to generate the dissociation path manually. For p38α, we generated the dissociation pathway using accelerated molecular dynamics (AMD) followed by conformational relaxing with short conventional molecular dynamics (MD), steered molecular dynamics (SMD) and manual pulling. We found that even for small β-CD complexes, different β-CD conformations will alter the height of the PMF and different dissociation directions result in appearance/disappearance of local minima. SMD poorly samples the residue sidechain movement, leading to overestimated height of PMF. On the other hand, the AMD pathway relaxed by short conventional MD sampled more accurate structures, resulting in reasonable PMF.

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 Free energy landscape for the entire transport cycle of triose-phosphate/phosphate translocator

2017 ◽  
Author(s):  
Mizuki Takemoto ◽  
Yongchan Lee ◽  
Ryuichiro Ishitani ◽  
Osamu Nureki
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Conformational Transition ◽  
Substrate Binding ◽  
Energy Landscape ◽  
Umbrella Sampling ◽  
Free Energy Landscape ◽  
Coupling Mechanism ◽  
Triose Phosphate ◽  
Phosphate Translocator

AbstractSecondary active transporters translocate their substrates using the electrochemical potentials of other chemicals, undergoing large-scale conformational changes. Despite extensive structural studies, the atomic details of the transport mechanism still remain elusive. Here we performed a series of all-atom molecular dynamics simulations of the triose-phosphate/phosphate translocator (TPT), which exports organic phosphates in the chloroplast stroma in strict counter exchange with inorganic phosphate (Pi). Biased sampling methods, including string method and umbrella sampling, successfully reproduced the conformational changes between the inward– and outward-facing states, along with the substrate binding. The free energy landscape of this entire TPT transition pathway demonstrated the alternating access and substrate translocation mechanisms, which revealed Pi is relayed by positively charged residues along the transition pathway. Furthermore, the conserved Glu207 functions as a “molecular switch”, linking the local substrate binding and the global conformational transition. Our results provide atomic-detailed insights into the energy coupling mechanism of antiporter.

scholarly journals An Efficient GaMD Multi-Level Enhanced Sampling Strategy: Application to Polarizable Force Fields Simulations of Large Biological Systems

2021 ◽  
Author(s):  
Fréderic Célerse ◽  
Theo Jaffrelot-Inizan ◽  
Louis Lagardère ◽  
Olivier Adjoua ◽  
Pierre Monmarché ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Adaptive Sampling ◽  
Sampling Strategy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Enhanced Sampling ◽  
Polarizable Force Field ◽  
Accelerated Molecular Dynamics ◽  
Polarizable Force Fields ◽  
Multi Level

We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups thanks to the use of fast multiple--timestep integrators. To further reduce time-to-solution, we couple GaMD to Umbrella Sampling (US). The GaMD—US/dual-water approach is tested on the 1D Potential of Mean Force (PMF) of the CD2-CD58 system (168000 atoms) allowing the AMOEBA PMF to converge within 1 kcal/mol of the experimental value. Finally, Adaptive Sampling (AS) is added enabling AS-GaMD capabilities but also the introduction of the new Adaptive Sampling--US--GaMD (ASUS--GaMD) scheme. The highly parallel ASUS--GaMD setup decreases time to convergence by respectively 10 and 20 compared to GaMD--US and US.

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