scholarly journals Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling

2020 ◽  
Vol 22 (1) ◽  
pp. 270
Author(s):  
Hisham M. Dokainish ◽  
Yuji Sugita
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Md Simulations ◽  
Conformational Sampling ◽  
Salt Bridges ◽  
Multidomain Proteins ◽  
Charged Residues ◽  
Ligand Interactions ◽  
Moving Domains ◽  
Domain Motions

Conformational transitions in multidomain proteins are essential for biological functions. The Apo conformations are typically open and flexible, while the Holo states form more compact conformations stabilized by protein-ligand interactions. Unfortunately, the atomically detailed mechanisms for such open-closed conformational changes are difficult to be accessed experimentally as well as computationally. To simulate the transitions using atomistic molecular dynamics (MD) simulations, efficient conformational sampling algorithms are required. In this work, we propose a new approach based on generalized replica-exchange with solute tempering (gREST) for exploring the open-closed conformational changes in multidomain proteins. Wherein, selected surface charged residues in a target protein are defined as the solute region in gREST simulation and the solute temperatures are different in replicas and exchanged between them to enhance the domain motions. This approach is called gREST selected surface charged residues (gREST_SSCR) and is applied to the Apo and Holo states of ribose binding protein (RBP) in solution. The conformational spaces sampled with gREST_SSCR are much wider than those with the conventional MD, sampling open-closed conformational changes while maintaining RBP domains’ stability. The free-energy landscapes of RBP in the Apo and Holo states are drawn along with twist and hinge angles of the two moving domains. The inter-domain salt-bridges that are not observed in the experimental structures are also important in the intermediate states during the conformational changes.

scholarly journals Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Balint Dudas ◽  
Daniel Toth ◽  
David Perahia ◽  
Arnaud B. Nicot ◽  
Erika Balog ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Normal Modes ◽  
Md Simulations ◽  
Conformational Space ◽  
Metabolizing Enzymes ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Excited Normal Modes

AbstractSulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.

scholarly journals An equilibrium constant pH molecular dynamics method for accurate prediction of pH-dependence in protein systems: Theory and application

2020 ◽  
Author(s):  
Ekaterina Kots ◽  
Derek M. Shore ◽  
Harel Weinstein
Keyword(s):  
Molecular Dynamics ◽  
Equilibrium Constant ◽  
Conformational Changes ◽  
Ph Dependence ◽  
Md Simulations ◽  
Water Soluble ◽  
Conformational Sampling ◽  
Ph Change ◽  
Constant Ph ◽  
Dynamics Simulations

ABSTRACTComputational modeling and simulation of biomolecular systems at their functional pH ranges requires an accurate approach to exploring the pH dependence of conformations and interactions. Here we present a new approach – the Equilibrium Constant pH (ECpH) method – to perform conformational sampling of protein systems in the framework of molecular dynamics simulations in an N, P, T-thermodynamic ensemble. The performance of ECpH is illustrated for two proteins with experimentally determined conformational responses to pH change: the small globular water-soluble bovine b-lactoglobulin (BBL), and the dimer transmembrane antiporter CLC-ec1 Cl−/H+. We show that with computational speeds comparable to equivalent canonical MD simulations we performed, the ECpH trajectories reproduce accurately the pH-dependent conformational changes observed experimentally in these two protein systems, some of which were not seen in the corresponding canonical MD simulations.Abstract FigureTable of Contents artwork

Molecular Dynamics Simulations of HLA-CW4-Β2M-KIR2DL1 Protein and Homology Modeling of a Complex Associated with Psoriasis Disease (HLA-CW6-Β 2M-KIR2DS1)

2021 ◽  
Author(s):  
Mansour H Almatarneh ◽  
Ahmad M Alqaisi ◽  
Enas K Ibrahim ◽  
Ghada G Kayed ◽  
Joshua W Hollett
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Complex Structure ◽  
3D Structure ◽  
Md Simulations ◽  
Salt Bridges ◽  
Small Peptide ◽  
Β2 Microglobulin ◽  
Dynamics Simulations ◽  
The Right

Molecular dynamics (MD) simulation was used to study the interactions of two immune proteins of HLA-Cw4-β2m-KIR2DL1 complex with small peptide QYDDAVYKL (nine amino acids) in an aqueous solution. This study aims to gain a detailed information about the conformational changes and the dynamics of the complex. The right parameters and force field for performing the MD simulations that was needed to calibrate the complex structure were determined. The non-bonded interactions (Electrostatic and van der Waals contributions), H-bond formation, and salt bridges between the ligand HLA-Cw4 and the receptor KIR2DL1 were estimated using the obtained MD trajectories. The buried surface area due to binding was calculated to get insight into the causes of specificity of receptor to ligand and explains mutations experiment. The study concluded that β2-microglobulin, one part of the complex, is not directly interacting with the peptide at the groove; therefore, it could be neglected from simulation. Our results showed that β2-microglobulin does not have any significant effect on the dynamics of the 3D-structure of the complex. This project will help in understanding to optimize candidate drug design, a small peptide that disrupts the interaction, for the optimal biological effect.

scholarly journals On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 99
Author(s):  
Cristian Privat ◽  
Sergio Madurga ◽  
Francesc Mas ◽  
Jaime Rubio-Martínez
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Md Simulations ◽  
Point Of View ◽  
Conformational Space ◽  
Conformational Sampling ◽  
Protonation State ◽  
Constant Ph ◽  
Biochemical Systems ◽  
Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

scholarly journals Enlighten2: molecular dynamics simulations of protein–ligand systems made accessible

2020 ◽  
Vol 36 (20) ◽  
pp. 5104-5106
Author(s):  
Kirill Zinovjev ◽  
Marc W van der Kamp
Keyword(s):  
Molecular Dynamics ◽  
Expert Knowledge ◽  
Structural Data ◽  
Md Simulations ◽  
Enzyme Engineering ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Dynamics Simulations ◽  
User Friendly ◽  
Dynamical Information

Abstract Motivation Experimental structural data can allow detailed insight into protein structure and protein–ligand interactions, which is crucial for many areas of bioscience, including drug design and enzyme engineering. Typically, however, little more than a static picture of protein–ligand interactions is obtained, whereas dynamical information is often required for deeper understanding and to assess the effect of mutations. Molecular dynamics (MD) simulations can provide such information, but setting up and running these simulations is not straightforward and requires expert knowledge. There is thus a need for a tool that makes protein–ligand simulation easily accessible to non-expert users. Results We present Enlighten2: efficient simulation protocols for protein–ligand systems alongside a user-friendly plugin to the popular visualization program PyMOL. With Enlighten2, non-expert users can straightforwardly run and visualize MD simulations on protein–ligand models of interest. There is no need to learn new programs and all underlying tools are free and open source. Availability and implementation The Enlighten2 Python package and PyMOL plugin are free to use under the GPL3.0 licence and can be found at https://enlighten2.github.io. We also provide a lightweight Docker image via DockerHub that includes Enlighten2 with all the required utilities.

scholarly journals A Virtual Reality Ensemble Molecular Dynamics Workflow to Study Complex Conformational Changes in Proteins

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
A Priori ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics

2019 ◽  
Vol 152 (1) ◽  
Author(s):  
Toshiko Yamazawa ◽  
Haruo Ogawa ◽  
Takashi Murayama ◽  
Maki Yamaguchi ◽  
Hideto Oyamada ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Hek293 Cells ◽  
Salt Bridges ◽  
Open Probability ◽  
Release Channel ◽  
Functional Studies ◽  
Function Relationship ◽  
Interdomain Interactions ◽  
Relationship Of

Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation–contraction coupling. Mutations in the RYR1 gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of CICR via RYR1. Thus far, &gt;300 mutations in RYR1 have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure–function relationship of mutant RYR1, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYR1 bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYR1 caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYR1s were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYR1 channel and provide insights into the mechanism of MH caused by the mutations at the NTD.

scholarly journals Combining Virtual Reality Visualization with Ensemble Molecular Dynamics to Study Complex Protein Conformational Changes

2020 ◽  
Author(s):  
Jordi Juárez-Jiménez ◽  
Philip Tew ◽  
Michael o'connor ◽  
Salome Llabres ◽  
Rebecca Sage ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Reality ◽  
Conformational Changes ◽  
Large Scale ◽  
Computational Cost ◽  
Md Simulations ◽  
Collective Variables ◽  
Protein Conformational Changes ◽  
Sampling Protocols ◽  
State Models

<p>Molecular dynamics (MD) simulations are increasingly used to elucidate relationships between protein structure, dynamics and their biological function. Currently it is extremely challenging to perform MD simulations of large-scale structural rearrangements in proteins that occur on millisecond timescales or beyond, as this requires very significant computational resources, or the use of cumbersome ‘collective variable’ enhanced sampling protocols. Here we describe a framework that combines ensemble MD simulations and virtual-reality visualization (eMD-VR) to enable users to interactively generate realistic descriptions of large amplitude, millisecond timescale protein conformational changes in proteins. Detailed tests demonstrate that eMD-VR substantially decreases the computational cost of folding simulations of a WW domain, without the need to define collective variables <i>a priori</i>. We further show that eMD-VR generated pathways can be combined with Markov State Models to describe the thermodynamics and kinetics of large-scale loop motions in the enzyme cyclophilin A. Our results suggest eMD-VR is a powerful tool for exploring protein energy landscapes in bioengineering efforts. </p>

scholarly journals Identification of Interactions of ABT-341 to Dipeptidyl Peptidase IV during Molecular Dynamics Simulations

2021 ◽  
Vol 7 (2) ◽  
pp. 91-98
Author(s):  
Enade Istyastono ◽  
Michael Gani
Keyword(s):  
Molecular Dynamics ◽  
Design Research ◽  
Hydrophobic Interactions ◽  
Md Simulations ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Structure Based Drug Design ◽  
Protein Ligand Interactions ◽  
Dpp Iv ◽  
Ligand Interactions

Background: Dipeptidyl Peptidase IV (DPP-IV) is an established drug discovery target for type 2 diabetes mellitus (T2DM) therapy. On the other hand, molecular dynamics (MD) simulations have been widely employed to obtain insights of the protein-ligand interactions in structure-based drug design research projects. Moreover, a software to identify protein-ligand interactions called PyPLIF HIPPOS was made publicly available recently. Employing PyPLIF HIPPOS to identify the interactions of DPP-IV and its ligand ABT-341 during MD simulations was then of considerable interest. Objectives: The main aim of this study was to identify protein-ligand interactions of ABT-341 to DPP-IV during MD simulations. Material and Methods: The crystal structure of DPP-IV co-crystallized with ABT-341 obtained from the Protein Data Bank with code of 2I78 was used as the main material. YASARA-Structure was employed for performing 10 ns prodution run MD simulations with snapshots in every 100 ps and PyPLIF HIPPOS was used to identify the protein-ligand interactions. Results: There were 23 interactions involving 13 residues identified by employing PyPLIF HIPPOS during the MD simulations. Two of them identified in all snapshots, i.e., hydrophobic interactions to PHE357 and TYR666. Conclusions: PyPLIF HIPPOS was succesfully employed to identify the interactions of ABT-341 to DPP-IV during MD simulations.

Molecular Basis Explanation of Imatinib Resistance of Bcr-Abl Due to T315I and P-Loop Mutations from Molecular Dynamics Simulations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2917-2917
Author(s):  
Tai-Sung Lee ◽  
Steven Potts ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Francis Giles ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Electrostatic Interactions ◽  
Large Scale ◽  
Resistance Mechanism ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Static Structure ◽  
Imatinib Resistance ◽  
Dynamics Simulations

Abstract Molecular dynamics (MD) simulations on the complex of imatinib with the wild-type, T315I, and other 10 P-loop mutants of the tyrosine kinase Bcr-Abl have been performed to study the imatinib resistance mechanism at the atomic level. MD simulations show that large scale computational simulations could offer insight information that a static structure or simple homology modeling methods cannot provide for studying the Bcr-Abl imatinib resistance problem, especially in the case of conformational changes due to remote mutations. By utilizing the Molecular Mechanics/Poisson-Boltzmann surface area (MM-PBSA) techniques and analyzing the interactions between imatinib and individual residues, imatinib resistance mechanisms not previously thought have been revealed. Non-directly contacted P-loop mutations either unfavorably change the direct electrostatic interactions with imatinib, or cause the conformational changes influencing the contact energies between imatinib and other non-P-loop residues. We demonstrate that imatinib resistance of T315I mainly comes from the breakdown of the interactions between imatinib and E286 and M290, contradictory to previously suggested that the missing hydrogen bonding is the main contribution. We also demonstrate that except for the mutations of the direct contact residues, such as L248 and Y253, the unfavorable electrostatic interaction between P-loop and imatinib is the main reason for resistance for the P-loop mutations. Furthermore, in Y255H, protonation of the histidin is essential for rendering this mutation resistant to Gleevec. Our results demonstrate that MD is a powerful way to verify and predict clinical response or resistance to imatinib and other potential drugs.

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