Allosteric Conformational Transition in Adenylate Kinase: Dynamic Correlations and Implication for Allostery

2010 ◽  
Vol 63 (3) ◽  
pp. 405 ◽  
Author(s):  
Ming S. Liu ◽  
Billy D. Todd ◽  
Richard J. Sadus
Keyword(s):  
Normal Mode ◽  
Conformational Changes ◽  
Adenylate Kinase ◽  
Conformational Transition ◽  
Normal Mode Analysis ◽  
Coarse Grained ◽  
Mode Analysis ◽  
Elastic Network Model ◽  
Protein Functions ◽  
Correlated Motion

An essential aspect of protein science is to determine the deductive relationship between structure, dynamics, and various sets of functions. The role of dynamics is currently challenging our understanding of protein functions, both experimentally and theoretically. To verify the internal fluctuations and dynamics correlations in an enzyme protein undergoing conformational transitions, we have applied a coarse-grained dynamics algorithm using the elastic network model for adenylate kinase. Normal mode analysis reveals possible dynamical and allosteric pathways for the transition between the open and the closed states of adenylate kinase. As the ligands binding induces significant flexibility changes of the nucleotides monophosphate (NMP) domain and adenosine triphosphate (ATP) domain, the diagonalized correlation between different structural transition states shows that most correlated motions occur between the NMP domain and the helices surrounding the ATP domain. The simultaneous existence of positive and negative correlations indicates that the conformational changes of adenylate kinase take place in an allosteric manner. Analyses of the cumulated normal mode overlap coefficients and long-range correlated motion provide new insights of operating mechanisms and dynamics of adenylate kinase. They also suggest a quantitative dynamics criterion for determining the allosteric cooperativity, which may be applicable to other proteins.

scholarly journals A force field for virtual atom molecular mechanics of proteins

2009 ◽  
Vol 106 (37) ◽  
pp. 15667-15672 ◽  
Author(s):  
Anil Korkut ◽  
Wayne A. Hendrickson
Keyword(s):  
Force Field ◽  
Molecular Mechanics ◽  
Normal Mode ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Coarse Grained ◽  
Mode Analysis ◽  
Biological Macromolecules ◽  
Molecular Mechanics Calculations ◽  
Low Degrees

Activities of many biological macromolecules involve large conformational transitions for which crystallography can specify atomic details of alternative end states, but the course of transitions is often beyond the reach of computations based on full-atomic potential functions. We have developed a coarse-grained force field for molecular mechanics calculations based on the virtual interactions of Cα atoms in protein molecules. This force field is parameterized based on the statistical distribution of the energy terms extracted from crystallographic data, and it is formulated to capture features dependent on secondary structure and on residue-specific contact information. The resulting force field is applied to energy minimization and normal mode analysis of several proteins. We find robust convergence in minimizations to low energies and energy gradients with low degrees of structural distortion, and atomic fluctuations calculated from the normal mode analyses correlate well with the experimental B-factors obtained from high-resolution crystal structures. These findings suggest that the virtual atom force field is a suitable tool for various molecular mechanics applications on large macromolecular systems undergoing large conformational changes.

scholarly journals Protein conformational transitions explored by a morphing approach based on normal mode analysis in internal coordinates

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258818
Author(s):  
Byung Ho Lee ◽  
Soon Woo Park ◽  
Soojin Jo ◽  
Moon Ki Kim
Keyword(s):  
Normal Mode ◽  
Conformational Changes ◽  
Degrees Of Freedom ◽  
Large Scale ◽  
Conformational Transition ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Theoretical Approaches ◽  
Internal Coordinates ◽  
Transition Pathways

Large-scale conformational changes are essential for proteins to function properly. Given that these transition events rarely occur, however, it is challenging to comprehend their underlying mechanisms through experimental and theoretical approaches. In this study, we propose a new computational methodology called internal coordinate normal mode-guided elastic network interpolation (ICONGENI) to predict conformational transition pathways in proteins. Its basic approach is to sample intermediate conformations by interpolating the interatomic distance between two end-point conformations with the degrees of freedom constrained by the low-frequency dynamics afforded by normal mode analysis in internal coordinates. For validation of ICONGENI, it is applied to proteins that undergo open-closed transitions, and the simulation results (i.e., simulated transition pathways) are compared with those of another technique, to demonstrate that ICONGENI can explore highly reliable pathways in terms of thermal and chemical stability. Furthermore, we generate an ensemble of transition pathways through ICONGENI and investigate the possibility of using this method to reveal the transition mechanisms even when there are unknown metastable states on rough energy landscapes.

A complex multiscale virtual particle model based elastic network model (CMVP-ENM) for the normal mode analysis of biomolecular complexes

2019 ◽  
Vol 21 (8) ◽  
pp. 4359-4366 ◽  
Author(s):  
D. Vijay Anand ◽  
Zhenyu Meng ◽  
Kelin Xia
Keyword(s):  
Normal Mode ◽  
Network Model ◽  
Material Properties ◽  
Normal Mode Analysis ◽  
Mode Analysis ◽  
Particle Model ◽  
Elastic Network Model ◽  
Elastic Network ◽  
Virtual Particle ◽  
Biomolecular Complexes

The CMVP-ENM for virus normal mode analysis. With a special ratio parameter, CMVP-ENM can characterize the multi-material properties of biomolecular complexes and systematically enhance or suppress the modes for different components.

scholarly journals STRUCTURE FLUCTUATIONS AND CONFORMATIONAL CHANGES IN PROTEIN BINDING

2012 ◽  
Vol 10 (02) ◽  
pp. 1241002 ◽  
Author(s):  
ANATOLY M. RUVINSKY ◽  
TATSIANA KIRYS ◽  
ALEXANDER V. TUZIKOV ◽  
ILYA A. VAKSER
Keyword(s):  
Conformational Changes ◽  
Protein Complexes ◽  
Normal Mode Analysis ◽  
Distribution Functions ◽  
Mode Analysis ◽  
Amino Acid Type ◽  
Dihedral Angles ◽  
Elastic Network Model ◽  
Centers Of Mass ◽  
Interface Residues

Structure fluctuations and conformational changes accompany all biological processes involving macromolecules. The paper presents a classification of protein residues based on the normalized equilibrium fluctuations of the residue centers of mass in proteins and a statistical analysis of conformation changes in the side-chains upon binding. Normal mode analysis and an elastic network model were applied to a set of protein complexes to calculate the residue fluctuations and develop the residue classification. Comparison with a classification based on normalized B-factors suggests that the B-factors may underestimate protein flexibility in solvent. Our classification shows that protein loops and disordered fragments are enriched with highly fluctuating residues and depleted with weakly fluctuating residues. Strategies for engineering thermostable proteins are discussed. To calculate the dihedral angles distribution functions, the configuration space was divided into cells by a cubic grid. The effect of protein association on the distribution functions depends on the amino acid type and a grid step in the dihedral angles space. The changes in the dihedral angles increase from the near-backbone dihedral angle to the most distant one, for most residues. On average, one fifth of the interface residues change the rotamer state upon binding, whereas the rest of the interface residues undergo local readjustments within the same rotamer.

scholarly journals A combined coarse-grained and all-atom simulation of TRPV1 channel gating and heat activation

2015 ◽  
Vol 145 (5) ◽  
pp. 443-456 ◽  
Author(s):  
Wenjun Zheng ◽  
Feng Qin
Keyword(s):  
Conformational Changes ◽  
Md Simulation ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Normal Mode Analysis ◽  
Coarse Grained ◽  
Mode Analysis ◽  
Structural Dynamic ◽  
Heat Activation

The transient receptor potential (TRP) channels act as key sensors of various chemical and physical stimuli in eukaryotic cells. Despite years of study, the molecular mechanisms of TRP channel activation remain unclear. To elucidate the structural, dynamic, and energetic basis of gating in TRPV1 (a founding member of the TRPV subfamily), we performed coarse-grained modeling and all-atom molecular dynamics (MD) simulation based on the recently solved high resolution structures of the open and closed form of TRPV1. Our coarse-grained normal mode analysis captures two key modes of collective motions involved in the TRPV1 gating transition, featuring a quaternary twist motion of the transmembrane domains (TMDs) relative to the intracellular domains (ICDs). Our transition pathway modeling predicts a sequence of structural movements that propagate from the ICDs to the TMDs via key interface domains (including the membrane proximal domain and the C-terminal domain), leading to sequential opening of the selectivity filter followed by the lower gate in the channel pore (confirmed by modeling conformational changes induced by the activation of ICDs). The above findings of coarse-grained modeling are robust to perturbation by lipids. Finally, our MD simulation of the ICD identifies key residues that contribute differently to the nonpolar energy of the open and closed state, and these residues are predicted to control the temperature sensitivity of TRPV1 gating. These computational predictions offer new insights to the mechanism for heat activation of TRPV1 gating, and will guide our future electrophysiology and mutagenesis studies.

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