11 research outputs found
Effect of the solvent on the conformational behavior of the alanine dipeptide deduced from MD simulations
In general, peptides do not exhibit a well-defined conformational profile in solution. However, despite the experimental blurred picture associated with their structure, compelling spectroscopic evidence shows that peptides exhibit local order. The conformational profile of a peptide is the result of a balance between intramolecular interactions between different atoms of the molecule and intermolecular interactions between atoms of the molecule and the solvent. Accordingly, the conformational profile of a peptide will change upon the properties of the solvent it is soaked. To get insight into the balance between intra- and intermolecular interactions on the conformational preferences of the peptide backbone we have studied the conformational profile of the alanine dipeptide in diverse solvents using molecular dynamics as sampling technique. Solvents studied include chloroform, methanol, dimethyl sulfoxide, water and N-methylacetamide. Different treatments of the solvent have been studied in the present work including explicit solvent molecules, a generalized Born model and using the bulk dielectric constant of the solvent. The diverse calculations identify four major conformations with different populations in the diverse solvents: the C7 eq only sampled in chloroform; the C5 or extended conformation; the polyproline (PII) conformation and the right-handed a-helix conformation (aR). The results of present calculations permit to analyze how the balance between intra- and intermolecular interactions explains the populations of the diverse conformations observed.Postprint (published version
Efficient model chemistries for peptides. I. Split-valence Gaussian basis sets and the heterolevel approximation in RHF and MP2
We present an exhaustive study of more than 250 ab initio potential energy
surfaces (PESs) of the model dipeptide HCO-L-Ala-NH2. The model chemistries
(MCs) used are constructed as homo- and heterolevels involving possibly
different RHF and MP2 calculations for the geometry and the energy. The basis
sets used belong to a sample of 39 selected representants from Pople's
split-valence families, ranging from the small 3-21G to the large
6-311++G(2df,2pd). The reference PES to which the rest are compared is the
MP2/6-311++G(2df,2pd) homolevel, which, as far as we are aware, is the more
accurate PES of a dipeptide in the literature. The aim of the study presented
is twofold: On the one hand, the evaluation of the influence of polarization
and diffuse functions in the basis set, distinguishing between those placed at
1st-row atoms and those placed at hydrogens, as well as the effect of different
contraction and valence splitting schemes. On the other hand, the investigation
of the heterolevel assumption, which is defined here to be that which states
that heterolevel MCs are more efficient than homolevel MCs. The heterolevel
approximation is very commonly used in the literature, but it is seldom
checked. As far as we know, the only tests for peptides or related systems,
have been performed using a small number of conformers, and this is the first
time that this potentially very economical approximation is tested in full
PESs. In order to achieve these goals, all data sets have been compared and
analyzed in a way which captures the nearness concept in the space of MCs.Comment: 54 pages, 16 figures, LaTeX, AMSTeX, Submitted to J. Comp. Che
Effect of the solvent on the conformational behavior of the alanine dipeptide deduced from MD simulations
In general, peptides do not exhibit a well-defined conformational profile in solution. However, despite the experimental blurred picture associated with their structure, compelling spectroscopic evidence shows that peptides exhibit local order. The conformational profile of a peptide is the result of a balance between intramolecular interactions between different atoms of the molecule and intermolecular interactions between atoms of the molecule and the solvent. Accordingly, the conformational profile of a peptide will change upon the properties of the solvent it is soaked. To get insight into the balance between intraand intermolecular interactions on the conformational preferences of the peptide backbone we have studied the conformational profile of the alanine dipeptide in diverse solvents using molecular dynamics as sampling technique. Solvents studied include chloroform, methanol, dimethyl sulfoxide, water and N-methylacetami de. Different treatments of the solvent have been studied in the present work including explicit solvent molecules, a generalized Born model and using the bulk dielectric constant of the solvent. The diverse calculations identify four major conformations with different populations in the diverse solvents: the C-7(eq) only sampled in chloroform; the C-5 or extended conformation; the polyproline (PII) conformation and the right-handed alpha-helix conformation (alpha(R)). The results of present calculations permit to analyze how the balance between intra- and intermolecular interactions explains the populations of the diverse conformations observed. (C) 2017 Elsevier Inc. All rights reserved
Quantum mechanical calculation of the effects of stiff and rigid constraints in the conformational equilibrium of the Alanine dipeptide
If constraints are imposed on a macromolecule, two inequivalent classical
models may be used: the stiff and the rigid one. This work studies the effects
of such constraints on the Conformational Equilibrium Distribution (CED) of the
model dipeptide HCO-L-Ala-NH2 without any simplifying assumption. We use ab
initio Quantum Mechanics calculations including electron correlation at the MP2
level to describe the system, and we measure the conformational dependence of
all the correcting terms to the naive CED based in the Potential Energy Surface
(PES) that appear when the constraints are considered. These terms are related
to mass-metric tensors determinants and also occur in the Fixman's compensating
potential. We show that some of the corrections are non-negligible if one is
interested in the whole Ramachandran space. On the other hand, if only the
energetically lower region, containing the principal secondary structure
elements, is assumed to be relevant, then, all correcting terms may be
neglected up to peptides of considerable length. This is the first time, as far
as we know, that the analysis of the conformational dependence of these
correcting terms is performed in a relevant biomolecule with a realistic
potential energy function.Comment: 37 pages, 4 figures, LaTeX, BibTeX, AMSTe
Peptide Bond Distortions from Planarity: New Insights from Quantum Mechanical Calculations and Peptide/Protein Crystal Structures
By combining quantum-mechanical analysis and statistical survey of peptide/protein structure databases we here report a thorough investigation of the conformational dependence of the geometry of peptide bond, the basic element of protein structures. Different peptide model systems have been studied by an integrated quantum mechanical approach, employing DFT, MP2 and CCSD(T) calculations, both in aqueous solution and in the gas phase. Also in absence of inter-residue interactions, small distortions from the planarity are more a rule than an exception, and they are mainly determined by the backbone ψ dihedral angle. These indications are fully corroborated by a statistical survey of accurate protein/peptide structures. Orbital analysis shows that orbital interactions between the σ system of Cα substituents and the π system of the amide bond are crucial for the modulation of peptide bond distortions. Our study thus indicates that, although long-range inter-molecular interactions can obviously affect the peptide planarity, their influence is statistically averaged. Therefore, the variability of peptide bond geometry in proteins is remarkably reproduced by extremely simplified systems since local factors are the main driving force of these observed trends. The implications of the present findings for protein structure determination, validation and prediction are also discussed
Explicit factorization of external coordinates in constrained Statistical Mechanics models
If a macromolecule is described by curvilinear coordinates or rigid
constraints are imposed, the equilibrium probability density that must be
sampled in Monte Carlo simulations includes the determinants of different
mass-metric tensors. In this work, we explicitly write the determinant of the
mass-metric tensor G and of the reduced mass-metric tensor g, for any molecule,
general internal coordinates and arbitrary constraints, as a product of two
functions; one depending only on the external coordinates that describe the
overall translation and rotation of the system, and the other only on the
internal coordinates. This work extends previous results in the literature,
proving with full generality that one may integrate out the external
coordinates and perform Monte Carlo simulations in the internal conformational
space of macromolecules. In addition, we give a general mathematical argument
showing that the factorization is a consequence of the symmetries of the metric
tensors involved. Finally, the determinant of the mass-metric tensor G is
computed explicitly in a set of curvilinear coordinates specially well-suited
for general branched molecules.Comment: 22 pages, 2 figures, LaTeX, AMSTeX. v2: Introduccion slightly
extended. Version in arXiv is slightly larger than the published on
A physically meaningful method for the comparison of potential energy functions
In the study of the conformational behavior of complex systems, such as
proteins, several related statistical measures are commonly used to compare two
different potential energy functions. Among them, the Pearson's correlation
coefficient r has no units and allows only semi-quantitative statements to be
made. Those that do have units of energy and whose value may be compared to a
physically relevant scale, such as the root mean square deviation (RMSD), the
mean error of the energies (ER), the standard deviation of the error (SDER) or
the mean absolute error (AER), overestimate the distance between potentials.
Moreover, their precise statistical meaning is far from clear. In this article,
a new measure of the distance between potential energy functions is defined
which overcomes the aforementioned difficulties. In addition, its precise
physical meaning is discussed, the important issue of its additivity is
investigated and some possible applications are proposed. Finally, two of these
applications are illustrated with practical examples: the study of the van der
Waals energy, as implemented in CHARMM, in the Trp-Cage protein (PDB code 1L2Y)
and the comparison of different levels of the theory in the ab initio study of
the Ramachandran map of the model peptide HCO-L-Ala-NH2.Comment: 30 pages, 7 figures, LaTeX, BibTeX. v2: A misspelling in the author's
name has been corrected. v3: A new application of the method has been added
at the end of section 9 and minor modifications have also been made in other
sections. v4: Journal reference and minor corrections adde
Introduction to protein folding for physicists
The prediction of the three-dimensional native structure of proteins from the
knowledge of their amino acid sequence, known as the protein folding problem,
is one of the most important yet unsolved issues of modern science. Since the
conformational behaviour of flexible molecules is nothing more than a complex
physical problem, increasingly more physicists are moving into the study of
protein systems, bringing with them powerful mathematical and computational
tools, as well as the sharp intuition and deep images inherent to the physics
discipline. This work attempts to facilitate the first steps of such a
transition. In order to achieve this goal, we provide an exhaustive account of
the reasons underlying the protein folding problem enormous relevance and
summarize the present-day status of the methods aimed to solving it. We also
provide an introduction to the particular structure of these biological
heteropolymers, and we physically define the problem stating the assumptions
behind this (commonly implicit) definition. Finally, we review the 'special
flavor' of statistical mechanics that is typically used to study the
astronomically large phase spaces of macromolecules. Throughout the whole work,
much material that is found scattered in the literature has been put together
here to improve comprehension and to serve as a handy reference.Comment: 53 pages, 18 figures, the figures are at a low resolution due to
arXiv restrictions, for high-res figures, go to http://www.pabloechenique.co