On the convergence of the conformational coordinates basis set obtained by the essential dynamics analysis of proteins' molecular dynamics simulations

Amadei, Andrea; Ceruso, Marc A.; Nola, Alfredo Di

doi:10.1002/(sici)1097-0134(19990901)36:4<419::aid-prot5>3.0.co;2-u

Cited by 288 publications

(247 citation statements)

References 14 publications

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“…The RMSIP measure 45 discussed in the Methods Section, eq 2.4, examines convergence by comparing the overlap of modes constructed by using different time intervals of the simulation. In our test, n ) 2 (the first two modes) and we take intervals increasing with a 100 ps stride until the intervals are 1 ns long.…”

Section: Resultsmentioning

confidence: 99%

“…The two intervals taken to compare with each other are always of same time length, with one starting at the beginning of the analysis time and the other from the end of this analysis time. This arrangement is used to reduce the possible correlation between the two time intervals 45 intended for comparison. Instead of using the RMSIP, we use its square because RMSIP 2 is a direct measure of the portion of the projection of the basis of one subspace onto the other subspace.…”

Section: Resultsmentioning

confidence: 99%

“…In Figure 5, we show the RMSIP 2 test for every system in DREMB and NoDREM. In the study of Amadei and co-workers, 45 they consider that an RMSIP around 0.6 (RMSIP 2 ) 0.36) represents good overlap for PCA analysis of convergence. In this sense, all the PCA results, both in DREMB and NoDREM, have good convergence except for the NoDREM at a distance 23 Å.…”

Section: Resultsmentioning

confidence: 99%

“…Several convergence tests have been proposed. [45][46][47] Amadei and coworkers 45 introduced a root-mean-square inner product (RMSIP) measure that evaluates the overlap of a subset of n modes, where the modes are obtained from different time intervals taken from the total trajectory. For example, time intervals t′ could be taken from the second half of the trajectory, starting from the end, and the other intervals of length t, taken from the first half of the trajectory starting from the beginning.…”

Section: Methodsmentioning

confidence: 99%

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Molecular Dynamics of Apo-Adenylate Kinase: A Distance Replica Exchange Method for the Free Energy of Conformational Fluctuations

2006

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A large domain motion in adenylate kinase from E. coli (AKE) is studied with molecular dynamics. AKE undergoes a large-scale rearrangement of its lid and AMP-binding domains when the open form closes over its substrates, AMP, and Mg 2+ -ATP, whereby the AMP-binding and lid domains come closer to the core. The third domain, the core, is relatively stable during this motion. A reaction coordinate that monitors the distance between the AMP-binding and core domains is selected to be able to compare with the results of energy transfer experiments. Sampling along this reaction coordinate is carried out by using a distance replica exchange method (DREM), where systems that differ by a restraint potential enforcing different reaction coordinate values are independently simulated with periodic attempts at exchange of these systems. Several methods are used to study the efficiency and convergence properties of the DREM simulation and compared with an analogous non-DREM simulation. The DREM greatly accelerates the rate and extent of configurational sampling and leads to equilibrium sampling as measured by monitoring collective modes obtained from a principal coordinate analysis. The potential of mean force along the reaction coordinate reveals a rather flat region for distances from the open to a relatively closed AKE conformation. The potential of mean force for smaller distances has a distinct minimum that is quite close to that found in the closed form X-ray structure. In concert with a decrease in the reaction coordinate distance (AMP-binding-to-core distance) the lid-to-core distance of AKE also decreases. Therefore, apo AKE can fluctuate from its open form to conformations that are quite similar to its closed form X-ray structure, even in the absence of its substrates.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Molecular Dynamics of Apo-Adenylate Kinase: A Distance Replica Exchange Method for the Free Energy of Conformational Fluctuations

2006

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“…Several convergence tests have been proposed. 50, 51 Amadei and co-workers 50 introduced a root-mean-square inner product (RMSIP) measure, that evaluates the overlap of a subset of n modes obtained from different time intervals of the total trajectory. Here, we take t and t′ to be two disjoint time intervals of the trajectory and use the resulting RMSIPs to monitor the stability of these modes.…”

Section: Methodsmentioning

confidence: 99%

Hamiltonian and Distance Replica Exchange Method Studies of Met-Enkephalin

Cukier

2007

J. Phys. Chem. B

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The conformational states of the zwitterionic form of the pentapeptide Met-enkephalin were explored with the use of explicit solvent molecular dynamics (MD). The N and C termini are ionized, as appropriate to polar solvent conditions, and consequently, there is a competition between open forms driven by polar solvation of the ammonium and carboxylate groups and closed forms driven by their salt-bridge formation. Normal MD started from an open state does not sample closed conformations. Sampling was enhanced with a distance replica exchange method (DREM) and with a Hamiltonian replica exchange method (HREM). The potential of mean force (PMF) along an end-to-end distance reaction coordinate was obtained with the DREM. The PMF shows a stable salt-bridge state and the presence of a large region of open states, as hypothesized for conformationally promiscuous small opiate peptides. The HREM systems differ by scaling the peptidepeptide and peptide-solvent electrostatic and Lennard-Jones potentials, with the goal of improving the sampling efficiency with a limited number of systems. A small number of systems were found to be sufficient to sample closed and open states. A principal component analysis (PCA) shows that the HREM-generated fluctuations are dominated by the first two principal modes. The first corresponds to the end-to-end reaction coordinate found in the DREM, and the first mode PMF is similar to the DREM PMF. The second mode describes the presence of two conformations, both of which correspond to the salt-bridge state distance. The conformers differ in the values of neighboring psi and phi dihedral angles, since such psi/phi compensation can still produce the same end-to-end distance. The two-dimensional PMF constructed from the first two PCA modes captures most of the significant backbone conformational space of Met-enkephalin.

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Global and local motions in ribonuclease A: A molecular dynamics study

Merlino

Vitagliano²,

Ceruso³

et al. 2002

Biopolymers

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The understanding of protein dynamics is one of the major goals of structural biology. A direct link between protein dynamics and function has been provided by x-ray studies performed on ribonuclease A (RNase A) (B. F. Rasmussen et al., Nature, 1992, Vol. 357, pp. 423-424; L. Vitagliano et al., Proteins: Structure, Function, and Genetics, 2002, Vol. 46, pp. 97-104). Here we report a 3 ns molecular dynamics simulation of RNase A in water aimed at characterizing the dynamical behavior of the enzyme. The analysis of local and global motions provides interesting insight on the dynamics/function relationship of RNase A. In agreement with previous crystallographic reports, the present study confirms that the RNase A active site is constituted by rigid (His12, Asn44, Thr45) and flexible (Lys41, Asp83, His119, Asp121) residues. The analysis of the global motions, performed using essential dynamics, shows that the two beta-sheet regions of RNase A move coherently in opposite directions, thus modifying solvent accessibility of the active site, and that the mixed alpha/3(10)-helix (residues 50-60) behaves as a mechanical hinge during the breathing motion of the protein. These data demonstrate that this motion, essential for RNase A substrate binding and release, is an intrinsic dynamical property of the ligand-free enzyme.

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On the convergence of the conformational coordinates basis set obtained by the essential dynamics analysis of proteins' molecular dynamics simulations

Cited by 288 publications

References 14 publications

Molecular Dynamics of Apo-Adenylate Kinase: A Distance Replica Exchange Method for the Free Energy of Conformational Fluctuations

Molecular Dynamics of Apo-Adenylate Kinase: A Distance Replica Exchange Method for the Free Energy of Conformational Fluctuations

Hamiltonian and Distance Replica Exchange Method Studies of Met-Enkephalin

Global and local motions in ribonuclease A: A molecular dynamics study

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