Reproducible Polypeptide Folding and Structure Prediction using Molecular Dynamics Simulations

Seibert, M.; Patriksson, Alexandra; Hess, Berk; Spoel, David van der

doi:10.1016/j.jmb.2005.09.030

Cited by 174 publications

(213 citation statements)

References 72 publications

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“…This raises questions in regard to the potential efficiency of the method for larger systems. We note in this regard that Seibert et al 39 have recently shown that for an 11-residue peptide in water simulations on the order of 200 ns at each temperature were required to reach convergence in terms of the melting curve. Thus, although T-REMD is much more efficient that conventional MD simulations for rapidly equilibrating systems, such as the ␤-heptapeptide in methanol considered here, alternative protocols may be needed to fold larger systems.…”

Section: Resultsmentioning

confidence: 91%

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

Periole

Mark

2007

The Journal of Chemical Physics

126

160

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Replica exchange methods (REMs) are increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. However, despite having been shown to be very effective on model systems, the application of REM in complex systems such as for the simulation of protein and peptide folding in explicit solvent has not been objectively tested in detail. Here we present a comparison of conventional MD and temperature replica exchange MD (T-REMD) simulations of a β-heptapeptide in explicit solvent. This system has previously been shown to undergo reversible folding on the time scales accessible to MD simulation and thus allows a direct one-to-one comparison of efficiency. The primary properties compared are the free energy of folding and the relative populations of different conformers as a function of temperature. It is found that to achieve a similar degree of precision T-REMD simulations starting from a random set of initial configurations were approximately an order of magnitude more computationally efficient than a single 800ns conventional MD simulation for this system at the lowest temperature investigated (275K). However, whereas it was found that T-REMD simulations are more than four times more efficient than multiple independent MD simulations at one temperature (300K) the actual increase in conformation sampling was only twofold. The overall gain in efficiency using REMD resulted primarily from the ordering of different conformational states over temperature, as opposed to a large increase of conformational sampling. It is also shown that in this system exchanges are accepted primarily based on (random) fluctuations within the solvent and are not strongly correlated with the instantaneous peptide conformation raising questions in regard to the efficiency of T-REMD in larger systems.

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Section: Resultsmentioning

confidence: 91%

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

Periole

Mark

2007

The Journal of Chemical Physics

126

160

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“…The REMD technique has been successfully used to obtain energy landscapes for the TRP cage and for the C-terminal β-hairpin of protein G, [20][21][22] to find the global minimum for chignolin 23 and to explore unfolding of α-helical peptides as a function of pressure and temperature. 24 REMD has also been used to explore intrafacial folding and membrane insertion of designed peptides 25 as well as simulations of DNA.…”

Section: Introductionmentioning

confidence: 99%

Computational Design and Experimental Discovery of an Antiestrogenic Peptide Derived from α-Fetoprotein

et al. 2007

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Breast cancer is the most common cancer among women, and tamoxifen is the preferred drug for estrogen receptor-positive breast cancer treatment. Many of these cancers are intrinsically resistant to tamoxifen or acquire resistance during treatment. Consequently, there is an ongoing need for breast cancer drugs that have different molecular targets. Previous work has shown that 8-mer and cyclic 9-mer peptides inhibit breast cancer in mouse and rat models, interacting with an unsolved receptor, while peptides smaller than eight amino acids did not. We show that the use of replica exchange molecular dynamics predicts the structure and dynamics of active peptides, leading to the discovery of smaller peptides with full biological activity. Simulations identified smaller peptide analogues with the same conserved reverse turn demonstrated in the larger peptides. These analogues were synthesized and shown to inhibit estrogen-dependent cell growth in a mouse uterine growth assay, a test showing reliable correlation with human breast cancer inhibition.

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“…Concerning the protein itself and its "quality" parameters, there does not seem to be any catastrophic "collapse" in structure (of the kind described (Seibert et al, 2005) for polypeptides, for example) apart from a slight decline in core packing as the simulation proceeds although the RMSD increases in a rather dramatic way, somewhat differently for the four cases. Common to all cases is a detectable correlation between the decline in solvation and in structural integrity as judged from the RMSD.…”

Section: Discussionmentioning

confidence: 87%

The fate of proteins in outer space

Seddon

Bywater

2015

International Journal of Astrobiology

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It is well established that any properly conducted biophysical studies of proteins must take appropriate account of solvent. For water-soluble proteins it has been an article of faith that water is largely responsible for stabilizing the fold, a notion that has recently come under increasing scrutiny. Further, there are some instances when proteins are studied experimentally in the absence of solvent, as in matrix-assisted laser desorption/ionization or electrospray mass spectrometry, for example, or in organic solvents for protein engineering purposes. Apart from these considerations, there is considerable speculation as to whether there is life on planets other than Earth, where conditions including the presence of water (both in liquid or vapor form and indeed ice), temperature and pressure may be vastly different from those prevailing on Earth. Mars, for example, has only 0.6% of Earth's mean atmospheric pressure which presents profound problems to protein structures, as this paper and a large corpus of experimental work demonstrate. Similar objections will most likely apply in the case of most exoplanets and other bodies such as comets whose chemistry and climate are still largely unknown.This poses the question, how do proteins survive in these different environments? In order to cast some light on these issues we have conducted a series of molecular dynamics simulations on protein dehydration under a variety of conditions. We find that, while proteins undergoing dehydration can retain their integrity for a short duration they ultimately become disordered, and we further show that the disordering can be retarded if superficial water is kept in place on the surface. These findings are compared with other published results on protein solvation in an astrobiological and astrochemical setting. Inter alia, our results suggest that there are limits as to what to expect in terms of the existence of possible extraterrestrial forms as well to what can be achieved in experimental investigations on living systems despatched from Earth. This finding may appear to undermine currently held hopes that life will be found on nearby planets, but it is important to be aware that the presence of ice and water are by themselves not sufficient; there has to be an atmosphere which includes water vapor at a sufficiently high partial pressure for proteins to be active. A possible scenario in which there has been a history of adequate water vapor pressure which allowed organisms to prepare for a future dessicated state by forming suitable protective capsules cannot of course be ruled out.

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Reproducible Polypeptide Folding and Structure Prediction using Molecular Dynamics Simulations

Cited by 174 publications

References 72 publications

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

Convergence and sampling efficiency in replica exchange simulations of peptide folding in explicit solvent

Computational Design and Experimental Discovery of an Antiestrogenic Peptide Derived from α-Fetoprotein

The fate of proteins in outer space

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