Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations

Abstract The dynamic structure of proteins is essential for their functions and may include large conformational transitions which can be studied by molecular dynamics (MD) simulations. However, details of these transitions are difficult to automatically track. To facilitate their analysis, we developed two scores of correlation between sidechain dihedral angles. The CIRCULAR and OMES scores are computed from, respectively, dihedral angle values and rotamer distributions. As a case study, we applied our methods to an activation-like transition of the chemokine receptor CXCR4, observed during accelerated MD simulations. The principal component analysis of the correlation matrices was consistent with the networking structure of the top ranking pairs. Both scores identify a set of residues whose “collaborative” sidechain rotamerization immediately preceded or accompanied the conformational transition of CXCR4. Detailed analysis of the sequential order of these rotamerizations suggests that an allosteric mechanism, involving the outward motion of an asparagine residue in transmembrane helix 3, might be a prerequisite to the large scale conformational transition of CXCR4. This case study provides the proof-of-concept that the correlation methods developed here are valuable exploratory techniques to help decipher complex reactional pathways.

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Deformation Behavior of Nanocrystalline Body-Centered Cubic Iron with Segregated, Foreign Interstitial: A Molecular Dynamics Study

Materials ◽

10.3390/ma13235351 ◽

2020 ◽

Vol 13 (23) ◽

pp. 5351

Author(s):

Ahmed Tamer AlMotasem ◽

Matthias Posselt ◽

Tomas Polcar

Keyword(s):

Molecular Dynamics ◽

Grain Boundary ◽

Deformation Behavior ◽

Large Scale ◽

Grain Boundary Sliding ◽

Carbon And Nitrogen ◽

Embedded Atom ◽

Boundary Sliding ◽

Dynamics Simulations

In the present work, modified embedded atom potential and large-scale molecular dynamics’ simulations were used to explore the effect of grain boundary (GB) segregated foreign interstitials on the deformation behavior of nanocrystalline (nc) iron. As a case study, carbon and nitrogen (about 2.5 at.%) were added to (nc) iron. The tensile test results showed that, at the onset of plasticity, grain boundary sliding mediated was dominated, whereas both dislocations and twinning were prevailing deformation mechanisms at high strain. Adding C/N into GBs reduces the free excess volume and consequently increases resistance to GB sliding. In agreement with experiments, the flow stress increased due to the presence of carbon or nitrogen and carbon had the stronger impact. Additionally, the simulation results revealed that GB reduction and suppressing GBs’ dislocation were the primary cause for GB strengthening. Moreover, we also found that the stress required for both intragranular dislocation and twinning nucleation were strongly dependent on the solute type.

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Visual Analytics for Deep Embeddings of Large Scale Molecular Dynamics Simulations

10.1101/830844 ◽

2019 ◽

Author(s):

Junghoon Chae ◽

Debsindhu Bhowmik ◽

Heng Ma ◽

Arvind Ramanathan ◽

Chad Steed

Keyword(s):

Molecular Dynamics ◽

Visual Analytics ◽

Large Scale ◽

Physical Phenomenon ◽

Living Organism ◽

Md Simulations ◽

High Dimensional ◽

Molecular Characteristics ◽

Complex Simulation ◽

Dynamics Simulations

AbstractMolecular Dynamics (MD) simulation have been emerging as an excellent candidate for understanding complex atomic and molecular scale mechanism of bio-molecules that control essential bio-physical phenomenon in a living organism. But this MD technique produces large-size and long-timescale data that are inherently high-dimensional and occupies many terabytes of data. Processing this immense amount of data in a meaningful way is becoming increasingly difficult. Therefore, specific dimensionality reduction algorithm using deep learning technique has been employed here to embed the high-dimensional data in a lower-dimension latent space that still preserves the inherent molecular characteristics i.e. retains biologically meaningful information. Subsequently, the results of the embedding models are visualized for model evaluation and analysis of the extracted underlying features. However, most of the existing visualizations for embeddings have limitations in evaluating the embedding models and understanding the complex simulation data. We propose an interactive visual analytics system for embeddings of MD simulations to not only evaluate and explain an embedding model but also analyze various characteristics of the simulations. Our system enables exploration and discovery of meaningful and semantic embedding results and supports the understanding and evaluation of results by the quantitatively described features of the MD simulations (even without specific labels).

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

Blood ◽

10.1182/blood.v110.11.2917.2917 ◽

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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Peptide Terminus Tilting: an Unusual conformational transition of MHC Class I Revealed by Molecular Dynamics Simulations

10.1101/219873 ◽

2017 ◽

Author(s):

Yeping Sun ◽

Po Tian

Keyword(s):

Molecular Dynamics ◽

Antigen Presentation ◽

Influenza A ◽

Conformational Transition ◽

Md Simulations ◽

Lymphocytic Choriomeningitis ◽

Class I ◽

Accelerated Molecular Dynamics ◽

Binding Pockets ◽

Dynamics Simulations

ABSTRACTA conventional picture for major histocompatibility complex class I (MHCI) antigen presentation is that the terminal anchor residues of the antigenic peptide bind to the pockets at the bottom of the MHC cleft, leaving the central peptide residues exposed for T cell antigen receptor (TCR) recognition. However, in the present study, we show that in canonical or accelerated molecular dynamics (MD) simulations, the peptide terminus in some immunodominant peptide-MHCI (pMHCI) complexes can detach from their binding pockets and stretch outside the MHC cleft. These pMHCI complexes include the complex of the H-2Kb and the lymphocytic choriomeningitis virus (LCMV) gp33 peptide, and the complex of the HLA-A*0201 and the influenza A virus M1 peptide. The detached peptide terminus becomes the most prominent spot at the pMHC interface, and so can serves as a novel TCR recognition target. Thus, peptide terminus detaching may be a novel mechanism for MHC antigen presentation.

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Molecular dynamics simulations disclose early stages of the photo-activation of cryptochrome 4

10.1101/324962 ◽

2018 ◽

Cited By ~ 1

Author(s):

D. R. Kattnig ◽

C. Nielsen ◽

I. A. Solov’yov

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Large Scale ◽

Conformational Dynamics ◽

Md Simulations ◽

Quantum Processes ◽

Helical Segment ◽

High Betweenness ◽

Dynamics Simulations ◽

Fad Binding

AbstractBirds appear to be equipped with a light-dependent, radical-pair-based magnetic compass that relies on truly quantum processes. While the identity of the sensory protein has remained speculative, cryptochrome 4 has recently been identified as the most auspicious candidate. Here, we report on allatom molecular dynamics (MD) simulations addressing the structural reorganisations that accompany the photoreduction of the flavin cofactor in a model of the European robin cryptochrome 4 (ErCry4). Extensive MD simulations reveal that the photo-activation of ErCry4 induces large-scale conformational changes on short (hundreds of nanoseconds) timescales. Specifically, the photo-reduction is accompanied with the release of the C-terminal tail, structural rearrangements in the vicinity of the FAD-binding site, and the noteworthy formation of an α-helical segment at the N-terminal part. Some of these rearrangements appear to expose potential phosphorylation sites. We describe the conformational dynamics of the protein using a graph-based approach that is informed by the adjacency of residues and the correlation of their local motions. This approach reveals densely coupled reorganisation communities, which facilitate an efficient signal transduction due to a high density of hubs. These communities are interconnected by a small number of highly important residues characterized by high betweenness centrality. The network approach clearly identifies the sites restructuring upon photoactivation, which appear as protrusions or delicate bridges in the reorganisation network. We also find that, unlike in the homologous cryptochrome from D. melanogaster, the release of the C-terminal domain does not appear to be correlated with the transposition of a histidine residue close to the FAD cofactor.

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Large-Scale Molecular Dynamics Simulations of Interstitial Defect Diffusion in Silicon

MRS Proceedings ◽

10.1557/proc-731-w9.10 ◽

2002 ◽

Vol 731 ◽

Cited By ~ 1

Author(s):

David A. Richie ◽

Jeongnim Kim ◽

Richard Hennig ◽

Kaden Hazzard ◽

Steve Barr ◽

...

Keyword(s):

Molecular Dynamics ◽

Large Scale ◽

Materials Science ◽

Tight Binding ◽

Md Simulations ◽

Binding Potential ◽

Interstitial Defect ◽

Long Time ◽

Computational Materials ◽

Dynamics Simulations

AbstractThe simulation of defect dynamics and evolution is a technologicaly relevant challenge for computational materials science. The diffusion of small defects in silicon unfolds as a sequence of structural transitions. The relative infrequency of transition events requires simulation over extremely long time scales. We simulate the diffusion of small interstitial clusters (I1, I2, I3) for a range of temperatures using large-scale molecular dynamics (MD) simulations with a realistic tight-binding potential. A total of 0.25 μ sec of simulation time is accumulated for the study. A novel real-time multiresolution analysis (RTMRA) technique extracts stable structures directly from the dynamics without structural relaxation. The discovered structures are relaxed to confirm their stability.

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Large-Scale Molecular Dynamics Simulations of Homogeneous Nucleation of Pure Aluminium

Metals ◽

10.3390/met9111217 ◽

2019 ◽

Vol 9 (11) ◽

pp. 1217 ◽

Cited By ~ 1

Author(s):

Papanikolaou ◽

Salonitis ◽

Jolly ◽

Frank

Keyword(s):

Molecular Dynamics ◽

Large Scale ◽

Solidification Process ◽

Md Simulations ◽

Pure Aluminium ◽

3 Dimensional ◽

Hexagonal Close Packed ◽

Simulation Domain ◽

Dynamics Simulations ◽

Insight Into

Despite the continuous and remarkable development of experimental techniques for the investigation of microstructures and the growth of nuclei during the solidification of metals, there are still unknown territories around this topic. The solidification in nanoscale can be effectively investigated by means of molecular dynamics (MD) simulations which can provide a deep insight into the mechanisms of the formation of nuclei and the induced crystal structures. In this study, MD simulations were performed to investigate the solidification of pure Aluminium and the effects of the cooling rate on the final properties of the solidified material. A large number of Aluminium atoms were used in order to investigate the grain growth over time and the formation of stacking faults during solidification. The number of face-centred cubic (FCC), hexagonal close-packed (HCP) and body-centred cubic (BCC) was recorded during the evolution of the process to illustrate the nanoscale mechanisms initiating solidification. The current investigation also focuses on the exothermic nature of the solidification process which has been effectively captured by means of MD simulations using 3 dimensional representations of the kinetic energy across the simulation domain.

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Role of Long-range Allosteric Communication in Determining the Stability and Disassembly of SARS-COV-2 in Complex with ACE2

10.1101/2020.11.30.405340 ◽

2020 ◽

Author(s):

Mauro L. Mugnai ◽

Clark Templeton ◽

Ron Elber ◽

D. Thirumalai

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Long Range ◽

Active Site ◽

Large Scale ◽

Conformational Transition ◽

Network Models ◽

Allosteric Communication ◽

The Stability ◽

Dynamics Simulations

AbstractSevere acute respiratory syndrome (SARS) and novel coronavirus disease (COVID-19) are caused by two closely related beta-coronaviruses, SARS-CoV and SARS-CoV-2, respectively. The envelopes surrounding these viruses are decorated with spike proteins, whose receptor binding domains (RBDs) initiate invasion by binding to the human angiotensin-converting enzyme 2 (ACE2). Subtle changes at the interface with ACE2 seem to be responsible for the enhanced affinity for the receptor of the SARS-CoV-2 RBD compared to SARS-CoV RBD. Here, we use Elastic Network Models (ENMs) to study the response of the viral RBDs and ACE2 upon dissassembly of the complexes. We identify a dominant detachment mode, in which the RBD rotates away from the surface of ACE2, while the receptor undergoes a conformational transition which stretches the active-site cleft. Using the Structural Perturbation Method, we determine the network of residues, referred to as the Allostery Wiring Diagram (AWD), which drives the large-scale motion activated by the detachment of the complex. The AWD for SARS-CoV and SARS-CoV-2 are remarkably similar, showing a network that spans the interface of the complex and reaches the active site of ACE2, thus establishing an allosteric connection between RBD binding and receptor catalytic function. Informed in part by the AWD, we used Molecular Dynamics simulations to probe the effect of interfacial mutations in which SARS-CoV-2 residues are replaced by their SARS-CoV counterparts. We focused on a conserved glycine (G502 in SARS-CoV-2, G488 in SARS-CoV) because it belongs to a region that initiates the dissociation of the complex along the dominant detachment mode, and is prominent in the AWD. Molecular Dynamics simulations of SARS-CoV-2 wild-type and G502P mutant show that the affinity for the human receptor of the mutant is drastically diminished. Our results suggest that in addition to residues that are in direct contact with the interface those involved in long range allosteric communication are also a determinant of the stability of the RBD-ACE2 complex.

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Big Data Approach to Large Scale Molecular Dynamics Simulations: Necessity and Inevitability for Drug Design

10.20944/preprints202109.0275.v1 ◽

2021 ◽

Author(s):

Dheeraj Chitara ◽

Sanjeev B. S.

Keyword(s):

Molecular Dynamics ◽

Big Data ◽

Drug Design ◽

Large Scale ◽

Md Simulations ◽

Complete Analysis ◽

Cloud Infrastructure ◽

Drug Receptor ◽

Dynamics Simulations ◽

Available Resources

Molecular Dynamics (MD) simulations model motion of molecules in atomistic detail and aid in drug design. While simulations on large systems may require several days to complete, analysis of terabytes of data generated in the process could also be time consuming. Recent studies captured exciting and dramatic drug-receptor interactions under cell-like complex conditions. Such advances make simulations of biomolecular interactions more realistic, insightful, and informative and have potential to make drug design more realistic. However, currently available resources and techniques do not provide, in reasonable time, a comprehensive understanding of events seen in simulations. We demonstrate that big data approach results in significant speedups, and provides rapid insights into simulations performed. Advancing this improvement, we propose a scalable, self-tuning, and responsive framework based on Cloud-infrastructure to accomplish the best possible MD studies with given priorities and within available resources.

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Sensitivity of Molecular Dynamics Simulations to Equilibration Scheme: A Case Study of Bromodomain Protein BRD4-Ligand Complex System

10.33774/chemrxiv-2021-dgzrt ◽

2021 ◽

Author(s):

Yunhui Ge ◽

Gaetano Calabro ◽

Christophe Bayly ◽

David Mobley

Keyword(s):

Complex System ◽

Molecular Dynamics ◽

Binding Site ◽

Md Simulations ◽

Careful Consideration ◽

Ligand Complex ◽

Thermodynamic Conditions ◽

Temperature And Pressure ◽

Dynamics Simulations

In molecular dynamics (MD) simulations, an equilibration phase is used to bring the system to the desired conditions (e.g. temperature and pressure) before collecting data in more extensive production phases. Ideally, the equilibration phase would bring the system to the correct equilibrium ensemble appropriate for the target thermodynamic conditions. Many studies give relatively little attention to details of the equilibration protocol as long as the system eventually reaches stabilization at the correct temperature, pressure, volume, etc. However, in a previous study we found a surprising instability of two ligands in a binding site. That led us to study the origin of this instability more, and in the present work we have traced it to details of the equilibration protocol. We found for the studied system, different equilibration schemes caused dramatic differences in sampled configurations of the system in production runs, highlighting the importance of careful consideration of equilibration schemes in MD simulations.

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