232 research outputs found
Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of the guanine sensing riboswitch
Riboswitches are a novel class of genetic control elements that function through the direct interaction of small metabolite molecules with structured RNA elements. The ligand is bound with high specificity and affinity to its RNA target and induces conformational changes of the RNA's secondary and tertiary structure upon binding. To elucidate the molecular basis of the remarkable ligand selectivity and affinity of one of these riboswitches, extensive all-atom molecular dynamics simulations in explicit solvent ({approx}1 µs total simulation length) of the aptamer domain of the guanine sensing riboswitch are performed. The conformational dynamics is studied when the system is bound to its cognate ligand guanine as well as bound to the non-cognate ligand adenine and in its free form. The simulations indicate that residue U51 in the aptamer domain functions as a general docking platform for purine bases, whereas the interactions between C74 and the ligand are crucial for ligand selectivity. These findings either suggest a two-step ligand recognition process, including a general purine binding step and a subsequent selection of the cognate ligand, or hint at different initial interactions of cognate and noncognate ligands with residues of the ligand binding pocket. To explore possible pathways of complex dissociation, various nonequilibrium simulations are performed which account for the first steps of ligand unbinding. The results delineate the minimal set of conformational changes needed for ligand release, suggest two possible pathways for the dissociation reaction, and underline the importance of long-range tertiary contacts for locking the ligand in the complex
Dynamic treatment of vibrational energy relaxation in a heterogeneous and fluctuating environment
A computational approach to describe the energy relaxation of a
high-frequency vibrational mode in a fluctuating heterogeneous environment is
outlined. Extending previous work [H. Fujisaki, Y. Zhang, and J.E. Straub, J.
Chem. Phys. {\bf 124}, 144910 (2006)], second-order time-dependent perturbation
theory is employed which includes the fluctuations of the parameters in the
Hamiltonian within the vibrational adiabatic approximation. This means that the
time-dependent vibrational frequencies along an MD trajectory are obtained via
a partial geometry optimization of the solute with fixed solvent and a
subsequent normal mode calculation. Adopting the amide I mode of
N-methylacetamide in heavy water as a test problem, it is shown that the
inclusion of dynamic fluctuations may significantly change the vibrational
energy relaxation. In particular, it is found that relaxation occurs in two
phases, because for short times ( 200 fs) the spectral density
appears continuous due to the frequency-time uncertainty relation, while at
longer times the discrete nature of the bath becomes apparent. Considering the
excellent agreement between theory and experiment, it is speculated if this
behavior can explain the experimentally obtained biphasic relaxation the amide
I mode of N-methylacetamide.Comment: 24 pages, 7 figures, submitted to J. Chem. Phy
Molecular dynamics simulation study of the binding of purine bases to the aptamer domain of the guanine sensing riboswitch
Riboswitches are a novel class of genetic control elements that function through the direct interaction of small metabolite molecules with structured RNA elements. The ligand is bound with high specificity and affinity to its RNA target and induces conformational changes of the RNA's secondary and tertiary structure upon binding. To elucidate the molecular basis of the remarkable ligand selectivity and affinity of one of these riboswitches, extensive all-atom molecular dynamics simulations in explicit solvent (≈1 μs total simulation length) of the aptamer domain of the guanine sensing riboswitch are performed. The conformational dynamics is studied when the system is bound to its cognate ligand guanine as well as bound to the non-cognate ligand adenine and in its free form. The simulations indicate that residue U51 in the aptamer domain functions as a general docking platform for purine bases, whereas the interactions between C74 and the ligand are crucial for ligand selectivity. These findings either suggest a two-step ligand recognition process, including a general purine binding step and a subsequent selection of the cognate ligand, or hint at different initial interactions of cognate and noncognate ligands with residues of the ligand binding pocket. To explore possible pathways of complex dissociation, various nonequilibrium simulations are performed which account for the first steps of ligand unbinding. The results delineate the minimal set of conformational changes needed for ligand release, suggest two possible pathways for the dissociation reaction, and underline the importance of long-range tertiary contacts for locking the ligand in the complex
Towards a Benchmark for Markov State Models: The Folding of HP35
Adopting a s-long molecular dynamics (MD) trajectory of the
reversible folding of villin headpiece (HP35) published by D. E. Shaw Research,
we recently constructed a Markov state model (MSM) of the folding process based
on interresidue contacts [J. Chem. Theory Comput. 2023, , 3391].
The model reproduces the MD folding times of the system and predicts that both
the native basin and the unfolded region of the free energy landscape are
partitioned into several metastable substates that are structurally well
characterized. Recognizing the need to establish well-defined but nontrivial
benchmark problems, in this Perspective we study to what extent and in what
sense this MSM may be employed as a reference model. To this end, we test the
robustness of the MSM by comparing it to models that use alternative
combinations of features, dimensionality reduction methods and clustering
schemes. The study suggests some main characteristics of the folding of HP35,
which should be reproduced by any other competitive model of the system.
Moreover, the discussion reveals which parts of the MSM workflow matter most
for the considered problem, and illustrates the promises and possible pitfalls
of state-based models for the interpretation of biomolecular simulations.Comment: arXiv admin note: text overlap with arXiv:2303.0381
Log-periodic oscillations as real-time signatures of hierarchical dynamics in proteins
The time-dependent relaxation of a dynamical system may exhibit a power-law
behavior that is superimposed by log-periodic oscillations. Sornette [Phys.
Rep. 297, 239 (1998)] showed that this behavior can be explained by a discrete
scale invariance of the system, which is associated with discrete and
equidistant timescales on a logarithmic scale. Examples include such diverse
fields as financial crashes, random diffusion, and quantum topological
materials. Recent time-resolved experiments and molecular dynamics simulations
suggest that discrete scale invariance may also apply to hierarchical dynamics
in proteins, where several fast local conformational changes are a prerequisite
for a slow global transition to occur. Employing entropy-based timescale
analysis and Markov state modeling to a simple one-dimensional hierarchical
model and biomolecular simulation data, it is found that hierarchical systems
quite generally give rise to logarithmically spaced discrete timescales. By
introducing a one-dimensional reaction coordinate that collectively accounts
for the hierarchically coupled degrees of freedom, the free energy landscape
exhibits a characteristic staircase shape with two metastable end states, which
causes the log-periodic time evolution of the system. The period of the
log-oscillations reflects the effective roughness of the energy landscape, and
can in simple cases be interpreted in terms of the barriers of the staircase
landscape
Path separation of dissipation-corrected targeted molecular dynamics simulations of protein-ligand unbinding
Protein-ligand (un)binding simulations are a recent focus of biased molecular
dynamics simulations. Such binding and unbinding can occur via different
pathways in and out of a binding site. We here present a theoretical framework
how to compute kinetics along separate paths and to combine the path-specific
rates into global binding and unbinding rates for comparison with experiment.
Using dissipation-corrected targeted molecular dynamics in combination with
temperature-boosted Langevin equation simulations [Nat. Commun. \textbf{11},
2918 (2020)] applied to a two-dimensional model and the trypsin-benzamidine
complex as test systems, we assess the robustness of the procedure and discuss
aspects of its practical applicability to predict multisecond kinetics of
complex biomolecular systems.Comment: This preprint is the unedited version of a manuscript that has been
sent to a scientific journal for consideration as a publication and can be
downloaded for private use only. Copyright with the journal and its publisher
after publicatio
Investigation of rare protein conformational transitions via dissipation-corrected targeted molecular dynamics
To sample rare events, dissipation-corrected targeted molecular dynamics
(dcTMD) applies a constant velocity constraint along a one-dimensional reaction
coordinate , which drives an atomistic system from an initial state into a
target state. Employing a cumulant approximation of Jarzynski's identity, the
free energy is calculated from the mean external work and
dissipated work of the process. By calculating the friction coefficient from the dissipated work, in a second step the equilibrium dynamics of the
process can be studied by propagating a Langevin equation. While so far dcTMD
has been mostly applied to study the unbinding of protein-ligand complexes,
here its applicability to rare conformational transitions within a protein and
the prediction of their kinetics is investigated. As this typically requires
the introduction of multiple collective variables , a
theoretical framework is outlined to calculate the associated free energy
and friction \matrix{\Gamma}(\vec{x}) from dcTMD
simulations along coordinate . Adopting the - transition of
alanine dipeptide as well as the open-closed transition of T4 lysozyme as
representative examples, the virtues and shortcomings of dcTMD to predict
protein conformational transitions and the related kinetics are studied.Comment: This preprint is the unedited version of a manuscript that has been
sent to a scientific journal for consideration as a publication and can be
downloaded for private use only. Copyright with the journal and its publisher
after publicatio
EFFECTOF THE IONTREATMENTONAN RNA HAIRPIN: MOLECULAR DYNAMICS STUDY
Molecular dynamics has been employed to study the effect of ion treatment on the stability of 14-nucleQtide RNA hairpin of Coxsackievirus B3. Three AMBER force fields were used: AMBER94, AMBER98, and AMBER99, which showed no significant structural difference of the hairpin. Thereafter, we applied two different long-range
electrostatic treatments that were reaction field and PME methods, and calculated the distribution of ions around the hairpin. Although the structural stabilities of the MD simulations using both methods were similar in 0.14 M Na+,ion environment around the hairpin was notably different. In particular, structural stabilition of the hairpin with increasing ion concentration and with ion Mi+ cannot be accommodated by simulations using reaction field method. Furthermore, the MD simulations using PME method suggested the strong similarity in structural and dynamical
properties of the hairpin with 0.14 M Na+,0.50 M Na+, 1.03M Na+,and 0.08 M Mi+ concentrations. However, the simulations ravea/eddifferent ion occupations of Na+and Mg
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