scholarly journals Making high-dimensional molecular distribution functions tractable through Belief Propagation on Factor Graphs

2021 ◽  
Author(s):  
Zachary Smith ◽  
Pratyush Tiwary
Keyword(s):  
Belief Propagation ◽  
Conformational Dynamics ◽  
Joint Probability ◽  
Md Simulations ◽  
Distribution Functions ◽  
Factor Graph ◽  
High Dimensional ◽  
Enhanced Sampling ◽  
Small Peptides ◽  
Approximate Probability

Molecular dynamics (MD) simulations provide a wealth of high-dimensional data at all-atom and femtosecond resolution but deciphering mechanistic information from this data is an ongoing challenge in physical chemistry and biophysics. Theoretically speaking, joint probabilities of the equilibrium distribution contain all thermodynamic information, but they prove increasingly difficult to compute and interpret as the dimensionality increases. Here, inspired by tools in probabilistic graphical modeling, we develop a factor graph trained through belief propagation that helps factorize the joint probability into an approximate tractable form that can be easily visualized and used. We validate the study through the analysis of the conformational dynamics of two small peptides with 5 and 9 residues. Our validations include testing the conditional dependency predictions through an intervention scheme inspired by Judea Pearl. Secondly we directly use the belief propagation based approximate probability distribution as a high-dimensional static bias for enhanced sampling, where we achieve spontaneous back-and-forth motion between metastable states that is up to 350 times faster than unbiased MD. We believe this work opens up useful ways to thinking about and dealing with high-dimensional molecular simulations.

scholarly journals Enhanced Sampling of Protein Conformational Transitions via Dynamically Optimized Collective Variables

2018 ◽  
Author(s):  
Z. Faidon Brotzakis ◽  
Michele Parrinello
Keyword(s):  
Degrees Of Freedom ◽  
Conformational Transition ◽  
Conformational Dynamics ◽  
Computational Cost ◽  
Md Simulations ◽  
Conformational Transitions ◽  
Enhanced Sampling ◽  
Collective Variables ◽  
Simulation Based ◽  
Combined Data

AbstractProtein conformational transitions often involve many slow degrees of freedom. Their knowledge would give distinctive advantages since it provides chemical and mechanistic insight and accelerates the convergence of enhanced sampling techniques that rely on collective variables. In this study, we implemented a recently developed variational approach to conformational dynamics metadynamics to the conformational transition of the moderate size protein, L99A T4 Lysozyme. In order to find the slow modes of the system we combined data coming from NMR experiments as well as short MD simulations. A Metadynamics simulation based on these information reveals the presence of two intermediate states, at an affordable computational cost.

Effect of Ionic Strength on the Aggregation Propensity of Aβ1-42 Peptide: An In-silico Study

2020 ◽  
Vol 14 (3) ◽  
pp. 216-226
Author(s):  
Priyanka Borah ◽  
Venkata S.K. Mattaparthi
Keyword(s):  
Diffusion Coefficient ◽  
Ionic Strength ◽  
Marked Effect ◽  
Computational Study ◽  
Conformational Dynamics ◽  
Rapid Change ◽  
Md Simulations ◽  
Radius Of Gyration ◽  
Aggregation Propensity ◽  
In Silico Study

Background: Aggregation of misfolded proteins under stress conditions in the cell might lead to several neurodegenerative disorders. Amyloid-beta (Aβ1-42) peptide, the causative agent of Alzheimer’s disease, has the propensity to fold into β-sheets under stress, forming aggregated amyloid plaques. This is influenced by factors such as pH, temperature, metal ions, mutation of residues, and ionic strength of the solution. There are several studies that have highlighted the importance of ionic strength in affecting the folding and aggregation propensity of Aβ1-42 peptide. Objective: To understand the effect of ionic strength of the solution on the aggregation propensity of Aβ1-42 peptide, using computational approaches. Materials and Methods: In this study, Molecular Dynamics (MD) simulations were performed on Aβ1-42 peptide monomer placed in (i) 0 M, (ii) 0.15 M, and (iii) 0.30 M concentration of NaCl solution. To prepare the input files for the MD simulations, we have used the Amberff99SB force field. The conformational dynamics of Aβ1-42 peptide monomer in different ionic strengths of the solutions were illustrated from the analysis of the corresponding MD trajectory using the CPPtraj tool. Results: From the MD trajectory analysis, we observe that with an increase in the ionic strength of the solution, Aβ1-42 peptide monomer shows a lesser tendency to undergo aggregation. From RMSD and SASA analysis, we noticed that Aβ1-42 peptide monomer undergoes a rapid change in conformation with an increase in the ionic strength of the solution. In addition, from the radius of gyration (Rg) analysis, we observed Aβ1-42 peptide monomer to be more compact at moderate ionic strength of the solution. Aβ1-42 peptide was also found to hold its helical secondary structure at moderate and higher ionic strengths of the solution. The diffusion coefficient of Aβ1-42 peptide monomer was also found to vary with the ionic strength of the solution. We observed a relatively higher diffusion coefficient value for Aβ1-42 peptide at moderate ionic strength of the solution. Conclusion: Our findings from this computational study highlight the marked effect of ionic strength of the solution on the conformational dynamics and aggregation propensity of Aβ1-42 peptide monomer.

scholarly journals Correlation of membrane protein conformational and functional dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raghavendar Reddy Sanganna Gari ◽  
Joel José Montalvo‐Acosta ◽  
George R. Heath ◽  
Yining Jiang ◽  
Xiaolong Gao ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Conformational Changes ◽  
Single Channel ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
High Temporal Resolution ◽  
Dependent Manner ◽  
Functional Dynamics ◽  
Ph Dependent ◽  
Open States

AbstractConformational changes in ion channels lead to gating of an ion-conductive pore. Ion flux has been measured with high temporal resolution by single-channel electrophysiology for decades. However, correlation between functional and conformational dynamics remained difficult, lacking experimental techniques to monitor sub-millisecond conformational changes. Here, we use the outer membrane protein G (OmpG) as a model system where loop-6 opens and closes the β-barrel pore like a lid in a pH-dependent manner. Functionally, single-channel electrophysiology shows that while closed states are favored at acidic pH and open states are favored at physiological pH, both states coexist and rapidly interchange in all conditions. Using HS-AFM height spectroscopy (HS-AFM-HS), we monitor sub-millisecond loop-6 conformational dynamics, and compare them to the functional dynamics from single-channel recordings, while MD simulations provide atomistic details and energy landscapes of the pH-dependent loop-6 fluctuations. HS-AFM-HS offers new opportunities to analyze conformational dynamics at timescales of domain and loop fluctuations.

scholarly journals Spontaneous and frequent conformational dynamics induced by A…A mismatch in d(CAA)·d(TAG) duplex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Kripi Tomar ◽  
D. Krishna Rao ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Mismatch Repair ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Base Flipping ◽  
Base Pairs ◽  
2D Noesy ◽  
Junction Formation ◽  
Nmr Techniques ◽  
Transient Events

AbstractBase pair mismatches in DNA can erroneously be incorporated during replication, recombination, etc. Here, the influence of A…A mismatch in the context of 5′CAA·5′TAG sequence is explored using molecular dynamics (MD) simulation, umbrella sampling MD, circular dichroism (CD), microscale thermophoresis (MST) and NMR techniques. MD simulations reveal that the A…A mismatch experiences several transient events such as base flipping, base extrusion, etc. facilitating B–Z junction formation. A…A mismatch may assume such conformational transitions to circumvent the effect of nonisostericity with the flanking canonical base pairs so as to get accommodated in the DNA. CD and 1D proton NMR experiments further reveal that the extent of B–Z junction increases when the number of A…A mismatch in d(CAA)·d(T(A/T)G) increases (1–5). CD titration studies of d(CAA)·d(TAG)n=5 with the hZαADAR1 show the passive binding between the two, wherein, the binding of protein commences with B–Z junction recognition. Umbrella sampling simulation indicates that the mismatch samples anti…+ syn/+ syn…anti, anti…anti & + syn…+ syn glycosyl conformations. The concomitant spontaneous transitions are: a variety of hydrogen bonding patterns, stacking and minor or major groove extrahelical movements (with and without the engagement of hydrogen bonds) involving the mismatch adenines. These transitions frequently happen in anti…anti conformational region compared with the other three regions as revealed from the lifetime of these states. Further, 2D-NOESY experiments indicate that the number of cross-peaks diminishes with the increasing number of A…A mismatches implicating its dynamic nature. The spontaneous extrahelical movement seen in A…A mismatch may be a key pre-trapping event in the mismatch repair due to the accessibility of the base(s) to the sophisticated mismatch repair machinery.

scholarly journals Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mei Dang ◽  
Yifan Li ◽  
Jianxing Song
Keyword(s):  
Conformational Dynamics ◽  
Md Simulations ◽  
Atp Binding ◽  
Rna Recognition Motif ◽  
Rna Recognition ◽  
Nucleic Acid Binding ◽  
General Role ◽  
Nmr Characterization ◽  
Lateral Sclerosis

AbstractTDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

scholarly journals Conformational Ensembles by NMR and MD Simulations in Model Heptapeptides with Select Tri-Peptide Motifs

2021 ◽  
Vol 22 (3) ◽  
pp. 1364
Author(s):  
V. V. Krishnan ◽  
Timothy Bentley ◽  
Alina Xiong ◽  
Kalyani Maitra
Keyword(s):  
Principal Component ◽  
Md Simulations ◽  
Conformational Space ◽  
Random Coil ◽  
Radius Of Gyration ◽  
Small Peptides ◽  
Conformational Ensembles ◽  
Solution State ◽  
Peptide Motifs ◽  
Explicit Solvent

Both nuclear magnetic resonance (NMR) and molecular dynamics (MD) simulations are routinely used in understanding the conformational space sampled by peptides in the solution state. To investigate the role of single-residue change in the ensemble of conformations sampled by a set of heptapeptides, AEVXEVG with X = L, F, A, or G, comprehensive NMR, and MD simulations were performed. The rationale for selecting the particular model peptides is based on the high variability in the occurrence of tri-peptide E*L between the transmembrane β-barrel (TMB) than in globular proteins. The ensemble of conformations sampled by E*L was compared between the three sets of ensembles derived from NMR spectroscopy, MD simulations with explicit solvent, and the random coil conformations. In addition to the estimation of global determinants such as the radius of gyration of a large sample of structures, the ensembles were analyzed using principal component analysis (PCA). In general, the results suggest that the -EVL- peptide indeed adopts a conformational preference that is distinctly different not only from a random distribution but also from other peptides studied here. The relatively straightforward approach presented herein could help understand the conformational preferences of small peptides in the solution state.

scholarly journals A Molecular Model of PEMFC Catalyst Layer: Simulation on Reactant Transport and Thermal Conduction

Membranes ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 148
Author(s):  
Wenkai Wang ◽  
Zhiguo Qu ◽  
Xueliang Wang ◽  
Jianfei Zhang
Keyword(s):  
Thermal Conductivity ◽  
Proton Exchange Membrane ◽  
Molecular Model ◽  
Phase Interface ◽  
Catalyst Layer ◽  
Md Simulations ◽  
Distribution Functions ◽  
Proton Exchange ◽  
Pt Catalyst ◽  
Reaction Efficiency

Minimizing platinum (Pt) loading while reserving high reaction efficiency in the catalyst layer (CL) has been confirmed as one of the key issues in improving the performance and application of proton exchange membrane fuel cells (PEMFCs). To enhance the reaction efficiency of Pt catalyst in CL, the interfacial interactions in the three-phase interface, i.e., carbon, Pt, and ionomer should be first clarified. In this study, a molecular model containing carbon, Pt, and ionomer compositions is built and the radial distribution functions (RDFs), diffusion coefficient, water cluster morphology, and thermal conductivity are investigated after the equilibrium molecular dynamics (MD) and nonequilibrium MD simulations. The results indicate that increasing water content improves water aggregation and cluster interconnection, both of which benefit the transport of oxygen and proton in the CL. The growing amount of ionomer promotes proton transport but generates additional resistance to oxygen. Both the increase of water and ionomer improve the thermal conductivity of the C. The above-mentioned findings are expected to help design catalyst layers with optimized Pt content and enhanced reaction efficiency, and further improve the performance of PEMFCs.

scholarly journals A molecular journey to check the conformational dynamics of tau tubulin kinase 2 mutations associated with Alzheimer's disease

RSC Advances ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 1320-1331
Author(s):  
Shahzaib Ahamad ◽  
Hema Kanipakam ◽  
Vijay Kumar ◽  
Dinesh Gupta
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Conformational Dynamics ◽  
Md Simulations

MD simulations of TTBK2 mutants to study its impact on stability of the protein.

scholarly journals Identification and Characterization of Novel Fc-Binding Heptapeptides from Experiments and Simulations

2018 ◽  
Author(s):  
Xiaoquan Sun ◽  
Justin Weaver ◽  
Sumith Ranil Wickramasinghe ◽  
Xianghong Qian
Keyword(s):  
Hydrophobic Interactions ◽  
Culture Media ◽  
Protein A ◽  
Md Simulations ◽  
Production Costs ◽  
Antibody Detection ◽  
Small Peptides ◽  
Affinity Ligands ◽  
Binding Behavior ◽  
Igg Isotypes

Purification of biologically-derived therapeutics is a major cost contributor to the production of this rapidly growing class of pharmaceuticals. Monoclonal antibodies comprise a large percentage of these products therefore new antibody purification tools are needed. Small peptides, as opposed to traditional antibody affinity ligands such as Protein A, may have advantages in stability and production costs. Multiple heptapeptides that demonstrate Fc binding behavior that have been identified from a combinatorial peptide library using M13 Phage Display are presented herein. Seven unique peptide sequences of diverse hydrophobicity and charge were identified. All seven peptides showed strong binding to the four major human IgG isotypes, human IgM, as well as binding to canine, rat, and mouse IgG. These seven peptides were also shown to bind human IgG4 from DMEM cell culture media with 5% FCS and 5 g/L ovalbumin present. These peptides may be useful as surface ligands for antibody detection and purification purposes. Molecular docking and classical molecular dynamics (MD) simulations were conducted to elucidate the mechanisms and energetics for the binding of these peptides to the Fc region. The binding site was found to be located between the two glycan chains inside the Fc fragment. Both hydrogen bonding and hydrophobic interactions were found to be crucial for the binding interactions. Excellent agreement for the binding strength was obtained between experimental results and simulations.

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