Potential of mean force calculations of ligand binding to ion channels from Jarzynski’s equality and umbrella sampling

2008 ◽  
Vol 128 (15) ◽  
pp. 155104 ◽  
Author(s):  
Turgut Baştuğ ◽  
Po-Chia Chen ◽  
Swarna M. Patra ◽  
Serdar Kuyucak
Keyword(s):  
Ion Channels ◽  
Ligand Binding ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Jarzynski’S Equality

scholarly journals Unraveling the substrate preference of an uncharacterized phylogenetic subgroup in Formate/Nitrite Transporter (FNT) family: Computational studies of anion transport inEscherichia coliFNT homolog

2019 ◽  
Author(s):  
Mishtu Mukherjee ◽  
Ramasubbu Sankararamakrishnan
Keyword(s):  
Ion Channels ◽  
Membrane Proteins ◽  
Drug Targets ◽  
Pathogenic Bacteria ◽  
Anion Channel ◽  
High Energy ◽  
Umbrella Sampling ◽  
Potential Of Mean Force ◽  
Ammonium Ion ◽  
Acidic Residues

AbstractFormate/Nitrite Transporters (FNTs) selectively transport monovalent anions and are found in prokaryotes and lowers eukaryotes. They play significant role in bacterial growth and act against the defense mechanism of infected host. Since FNTs don’t occur in higher animals, they are attractive drug targets for many bacterial diseases. Phylogenetic analysis revealed that they can be classified into eight subgroups and two of which belong to the uncharacterized YfdC-α and YfdC-β groups. Experimentally determined structures of FNTs belonging to different phylogenetic groups adopt the unique aquaporin-like hourglass helical fold. We considered formate channel fromVibrio Cholerae(VcFocA), hydrosulphide channel fromClostridium difficile(CdHSC) and the uncharacterized channel fromEscherchia coli(EcYfdC) to investigate the mechanism of transport and selectivity. Using equilibrium molecular dynamics (MD) and umbrella sampling studies, we determined temporal channel radius profiles, permeation events and potential of mean force (PMF) profiles of different substrates with the conserved central histidine residue in protonated or neutral form. Unlike the VcFocA and CdHSC, MD studies showed that the formate substrate was unable to enter the vestibule region of EcYfdC. Absence of a conserved basic residue and presence of acidic residues in the vestibule regions, conserved only in YfdC-α, were found to be responsible for high energy barriers for the anions to enter EcYfdC. PMF profiles generated for ammonia and ammonium ion revealed that EcYfdC can transport neutral solutes and could possibly be involved in the transport of cations analogous to the mechanism proposed for ammonium transporters. Although YfdC members belong to the FNT family, our studies convincingly reveal that EcYfdC is not an anion channel. Absence/presence of specific charged residues at particular positions makes EcYfdC selective for neutral or possibly cationic substrates. This adds to the repertoire of membrane proteins that use the same fold but transport substrates with different chemical nature.Author SummaryChannels and transporters are membrane proteins involved in the transport of solutes selectively across the cell membranes. Drugs for many diseases have been developed to inhibit ion channels. Formate/Nitrite Transporters (FNTs) are ion channels selective for monovalent anions and are present in bacteria and lower eukaryotes. Absence of FNTs in humans makes them as attractive drug targets against many pathogenic bacteria. To develop inhibitors for a protein, it is important to understand the mechanism of its function. Selectivity and transport mechanism of FNTs have been investigated for some members. One of the subgroups of FNTs, YfdC-α, is uncharacterized. In this study we used computer simulation approach to investigate the molecular mechanism of selectivity and transport of three FNTs including one from YfdC-α group fromEscherichia coli. Our studies show thatE. coliYfdC is not an anion channel although it belongs to FNT family. We hypothesize that the YfdC-α members could be involved in the transport of neutral or possibly cationic substrates. This is further supported by the conservation of specific acidic residues found only in YfdC-α in the vestibule regions. This finding has major implications in developing blockers for FNT members belonging to YfdC-α group.

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.

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

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

We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs -accelerated implementation within Tinker-HP. For the specific use with the flexible AMOEBA polarizable force field (PFF), we introduce the new "dual–water" GaMD mode. By adding harmonic boosts to the water stretching and bonding terms, it accelerates the solvent-solute interactions while enabling speedups with 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.

Molecular theory of solvation for supramolecules and soft matter structures: application to ligand binding, ion channels, and oligomeric polyelectrolyte gelators

Soft Matter ◽  
2012 ◽  
Vol 8 (5) ◽  
pp. 1508-1520 ◽  
Author(s):  
Andriy Kovalenko ◽  
Alexander E. Kobryn ◽  
Sergey Gusarov ◽  
Olga Lyubimova ◽  
Xiangjun Liu ◽  
...  
Keyword(s):  
Ion Channels ◽  
Ligand Binding ◽  
Soft Matter ◽  
Molecular Theory
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