Interplay of charge distribution and conformation in peptides: comparison of theory and experiment (original) (raw)
Related papers
Journal of Separation Science, 2008
Using electrophoretic mobility and bead modeling to characterize the charge and secondary structure of peptides Using a modeling methodology developed in our laboratory previously, the free solution electrophoretic mobilities of several peptides are examined to see what they can tell us about: (i) the pK a s of specific side groups, and (ii) possible secondary structure. Modeling is first applied to mobility versus pH data of several small peptides (Messana, I. et al., J. Chromatogr. B 1997, 699, 149) where the only adjustable parameter associated with the charge state of the peptide is the pK a of the C-terminal. In addition to examining this parameter, the question of possible secondary structure is addressed. For two of the peptides considered, GGNA and GGQA, it is possible to account for the observed mobilities using "random" models with little restriction on the allowed range of Phi -Psi angles. For GGRA and RPPGF, "compact" models (possibly involving an I-turn) must be used to match modeling mobilities with experiment. Finally, three more complicated peptides ranging in size from 15 to 20 amino acids are also examined and characterized (Sitaram, B. R. et al., J. Chromatogr. A 1999, 857, 263). Here also, we find evidence of I-turns or some other "compact" structure in two of the three peptides examined.
Force Field Modeling of Amino Acid Conformational Energies
Journal of Chemical Theory and Computation, 2007
The conformational degrees of freedom for four amino acids in a model peptide environment have been sampled with density functional and second-order Møller-Plesset methods. Geometries have been optimized with an augmented double-basis set and relative energies estimated by extrapolation of results using double, triple, and quadruple-basis sets and including higher order correlation effects. In addition, the effects of vibrational zero point energies and solvation have been considered. The density functional method is unable to locate all the minima found at the MP2 level, which most likely is due to the inability for describing dispersion interactions. The use of basis sets smaller than augmented polarized double-with the MP2 method may also in some cases lead to artifacts. The effects on relative energies by enlarging the basis set beyond an augmented triple-and including higher order correlation beyond MP2 is small. The MP2/aug-cc-pVTZ level is recommended as a level of theory capable of an accuracy of ∼1 kJ/mol for relative conformational energies. Eight different force fields are tested for reproducing the electronic structure reference data. Force fields that represent the electrostatic energy by fixed partial charges typically only account for half of the conformations, while the AMOEBA force field, which includes multipole moments and polarizability, can reproduce ∼80% of the conformations in terms of geometry. This not only suggests that multipole moments and polarizability are important factors in designing new force fields but also indicates that there is still room for improvements.
Quantitative Prediction of Charge Regulation in Oligopeptides
Weak ampholytes are ubiquitous in nature and commonly found in artificial pH-responsive systems. However, our limited understanding of their charge regulation and the lack of predictive capabilities hinder the bottom-up design of such systems. Here, we used a coarse-grained model of a flexible polymer with weakly ionisable monomer units to quantitatively analyse the ionisation behaviour of two oligopeptides. Our model predicts differences in the charge states between oligopeptides and monomeric amino acids, showing that conformational flexibility and electrostatic interactions between weak acid and base side chains play a key role in the charge regulation. By comparing our simulations with experimental results from potentiometric titration, capillary zone electrophoresis and NMR, we demonstrated that our model reliably predicts the charge state of various peptide sequences. Ultimately, our model is the first step towards understanding the charge regualtion in flexible disordered pro...
Conformations, Energetics, and Kinetics of Peptides in Membrane Environment
Chapter1 : We present the exact solution of a microscopic statistical mechanical model for the transformation of a long polypeptide between an unstructured coil conformation and an α-helix conformation. The polypeptide is assumed to be adsorbed to the interface between a polar and a non-polar environment such as realized by water and the lipid bilayer of a membrane. The interfacial coil-helix transformation is the first stage in the folding process of helical membrane proteins. Depending on the values of model parameters, the conformation changes as a crossover, a discontinuous transition, or a continuous transition with helicity in the role of order parameter. Our model is constructed as a system of statistically interacting quasiparticles that are activated from the helix pseudo-vacuum. The particles represent links between adjacent residues in coil conformation that form a self-avoiding random walk in two dimensions. Explicit results are presented for helicity, entropy, heat capacity, and the average numbers and sizes of both coil and helix segments. Chapter 2: We investigate profiles of local attributes (densities of entropy, enthalpy, free energy, and helicity) for the backbone of long polypeptides in the heterogeneous environment of a lipid bilayer or cell membrane. From these profiles we infer landscapes of global attributes for the backbone of short peptides with given position and orientation in that environment. Our methodology interprets the broken internal H-bonds along the backbone of the polypeptide as statistically interacting quasiparticles activated from the helix reference state. The interaction depends on the local environment (ranging from polar to non-polar), in particular on the availability of external H-bonds (with H 2 O molecules or lipid headgroups) to replace internal H-bonds. The helicity landscape in particular is an essential prerequisite for the continuation of this part of the project with focus on the side-chain contributions to the free-energy landscapes. The full free-energy landscapes are expected to yield information on insertion conditions and likely insertion pathways. Chapter 3: We present the first part in the design of a kinetic model for the insertion of short peptides, including variants of pHLIP, into a lipid bilayer. The process under scrutiny combines a transport phenomenon and a change in protonation status of negatively charged sites near the C terminus. The two kinetic phenomena influence each other and set different time scales. Processes with a significant range of time scales, known to be a challenge for molecular dynamics simulations, are shown to be within the scope of the kinetic modeling presented here, which is based on interlocking Markov chain processes. The two processes governing protonation status and transport are run individually and then in combination. This makes it possible to investigate feedback mechanisms between the two component processes. ACKNOWLEDGMENTS First and foremost, I want to thank my advisor Professor Gerhard Müller. It has been an honor to be his Ph.D. student. Prof. Müller provided me with every bit of guidance, assistance, and expertise throughout my studies. I would like to thank our experimental collaborators Professors Yana Reshetnyak and Oleg Andreev of URI for their valuable suggestions in all the projects that we have collaborated. Specifically, I would like to thank Prof. Reshetnyak for her continued support and for providing me the access of her Laboratory. I would like to thank my friend, Slaybaugh Gregory, for his great support and help during my quest of learning biophysical experiments. I would also like to thank my colleague, Aaron Mayer, for important discussions and suggestions. I also extend my gratitude to Professor David Freeman for his great support and invaluable advice. I am thankful to Prof. Leonard M. Kahn, Graduate Program Director, for his help, kindness, and guidance during my Ph.D. years. I am deeply indebted to him. I am also grateful to Prof. David Chelidze for his support, insightful comments and time. I would especially like to express my deepest gratitude to all my family members and friends. This dissertation would not have been possible without their warm love, continued patience, and endless support. More specifically, I would like to thank and dedicate this dissertation to my my late Mom, Nirjala Sharma, and Dad, Janak P. Sharma, for their love and inspiration throughout my life. I must express my gratitude to my wife, Gita, for her continued support throughout this experience. To my beloved daughter Garima and son Gaurav, I would like to express my thanks for being good kids always cheering me up. Finally, I would like to thank to my brother, Parashuram Upadhyaya, who originally ignited my passion for science and thirst for knowledge.
Aggregation dynamics of charged peptides in water: Effect of salt concentration
The Journal of Chemical Physics, 2019
Extensive molecular dynamics simulations have been employed to probe the effects of salts on the kinetics and dynamics of early-stage aggregated structures of steric zipper peptides in water. The simulations reveal that the chemical identity and valency of cation in the salt play a crucial role in aggregate dynamics and morphology of the peptides. Sodium ions induce the most aggregated structures, but this is not replicated equivalently by potassium ions which are also monovalent. Divalent magnesium ions induce aggregation but to a lesser extent than that of sodium, and their interactions with the charged peptides are also significantly different. The aggregate morphology in the presence of monovalent sodium ions is a compact structure with interpenetrating peptides, which differs from the more loosely connected peptides in the presence of either potassium or magnesium ions. The different ways in which the cations effectively renormalize the charges of peptides are suggested to be the cause of the differential effects of different salts studied here. These simulations underscore the importance of understanding both the valency and nature of salts in biologically relevant aggregated structures.
Journal of Chemical Theory and Computation, 2015
Understanding the intrinsic conformational preferences of amino acids and the extent to which they are modulated by neighboring residues is a key issue for developing predictive models of protein folding and stability. Here we present the results of 441 independent explicit-solvent MD simulations of all possible two-residue peptides that contain the 20 standard amino acids with histidine modeled in both its neutral and protonated states. 3 JHNH α coupling constants and δH α chemical shifts calculated from the MD simulations correlate quite well with recently published experimental measurements for a corresponding set of two-residue peptides. Neighboring residue effects (NREs) on the average 3 JHNH α and δH α values of adjacent residues are also reasonably well reproduced, with the large NREs exerted experimentally by aromatic residues, in particular, being accurately captured. NREs on the secondary structure preferences of adjacent amino acids have been computed and compared with corresponding effects observed in a coil library and the average β-turn preferences of all amino acid types have been determined. Finally, the intrinsic conformational preferences of histidine, and its NREs on the conformational preferences of adjacent residues, are both shown to be strongly affected by the protonation state of the imidazole ring.
Proteins: Structure, Function, and Bioinformatics, 2003
We compare the conformational distributions of Ace-Ala-Nme and Ace-Gly-Nme sampled in long simulations with several molecular mechanics (MM) force fields and with a fast combined quantum mechanics/molecular mechanics (QM/MM) force field, in which the solute's intramolecular energy and forces are calculated with the self-consistent charge density functional tight binding method (SCCDFTB), and the solvent is represented by either one of the well-known SPC and TIP3P models. All MM force fields give two main states for Ace-Ala-Nme,  and ␣ separated by free energy barriers, but the ratio in which these are sampled varies by a factor of 30, from a high in favor of  of 6 to a low of 1/5. The frequency of transitions between states is particularly low with the amber and charmm force fields, for which the distributions are noticeably narrower, and the energy barriers between states higher. The lower of the two barriers lies between ␣ and  at values of near 0 for all MM simulations except for charmm22. The results of the QM/MM simulations vary less with the choice of MM force field; the ratio /␣ varies between 1.5 and 2.2, the easy pass lies at near 0, and transitions between states are more frequent than for amber and charmm, but less frequent than for cedar. For Ace-Gly-Nme, all force fields locate a diffuse stable region around ؍ and ؍ , whereas the amber force field gives two additional densely sampled states near ؍ ؎100°and ؍ 0, which are also found with the QM/MM force field. For both solutes, the distribution from the QM/MM simulation shows greater similarity with the distribution in highresolution protein structures than is the case for any of the MM simulations. Proteins 2003;50:451-463.
Biophysical Journal, 1997
A method for combining calculations of residue pKa'S with changes in the position of polar hydrogens has been developed. The Boltzmann distributions of proton positions in hydroxyls and neutral titratable residues are found in the same Monte Carlo sampling procedure that determines the amino acid ionization states at each pH. Electrostatic, Lennard-Jones potentials, and torsion angle energies are considered at each proton position. Many acidic and basic residues are found to have significant electrostatic interactions with either a wateror hydroxyl-containing side chain. Protonation state changes are coupled to reorientation of the neighboring hydroxyl dipoles, resulting in smaller free energy differences between neutral and ionized residues than when the protein is held rigid. Multiconformation pH titration gives better agreement with the experimental pKa's for triclinic hen egg lysozyme than conventional rigid protein calculations. The hydroxyl motion significantly increases the protein dielectric response, making it sensitive to the composition of the local protein structure. More than one conformer per residue is often found at a given pH, providing information about the distribution of low-energy lysozyme structures. GLOSSARY II ionized form of ionizable group (side chain of Asp, Glu, Tyr, Arg, Lys, His, and the N and C termini of the polypeptide chain (CTR, NTR)) NI neutral form of ionizable group MP multiconformation polar group (buried waters and side chains of Ser, Thr) FP fixed polar group (back-bone amide and side chains of Asn, Gln, Met, Trp, Cys) pKint, i the apparent pKa of group i including reaction field energy, interaction with fixed polar groups and backbone and nonelectrostatic energy Interconvertions of energy units 1 ApK unit = 1.36 kcal/mol = 2.3OkT.
Molecular dynamics simulation and conformational analysis of some catalytically active peptides
Journal of Molecular Modeling, 2015
The design of stable and inexpensive artificial enzymes with potent catalytic activity is a growing field in peptide science. The first step in this design process is to understand the key factors that can affect the conformational preference of an enzyme and correlate them with its catalytic activity. In this work, molecular dynamics simulations in explicit water of two catalytically active peptides (peptide 1: Fmoc-Phe 1 -Phe 2 -His-CONH 2 ; peptide 2: Fmoc-Phe 1 -Phe 2 -Arg-CONH 2 ) were performed at temperatures of 300, 400, and 500 K. Conformational analysis of these peptides using Ramachandran plots identified the secondary structures of the amino acid residues involved (Phe 1 , Phe 2 , His, Arg) and confirmed their conformational flexibility in solution. Furthermore, Ramachandran maps revealed the intrinsic preference of the constituent residues of these compounds for a helical conformation. Long-range interaction distances and radius of gyration (R g ) values obtained during 20 ns MD simulations confirmed their tendency to form folded conformations. Results showed a decrease in side-chain (Phe 1 , Phe 2 , His ring, and Arg) contacts as the temperature was raised from 300 to 400 K and then to 500 K. Finally, the radial distribution functions (RDF) of the water molecules around the nitrogen atoms in the catalytically active His and Arg residues of peptide 1 and peptide 2 revealed that the strongest water-peptide interaction occurred with the arginine nitrogen atoms in peptide 2. Our results highlight differences in the secondary structures of the two peptides that can be explained by the different arrangement of water molecules around the nitrogen atoms of Arg in peptide 2 as compared to the arrangement of water molecules around the nitrogen atoms of His in peptide 1. The results of this work thus provide detailed insight into peptide conformations which can be exploited in the future design of peptide analogs.
Biopolymers, 2005
The changes in the partial molar volume (PMV) associated with the conformational transition of an alanine-rich peptide AK16 from the a-helix structure to various random coil structures are calculated by the three-dimensional interaction site model (3D-RISM) theory coupled with the Kirkwood-Buff theory. The volume change is analyzed by decomposing it into contributions from geometry and hydration: the changes in the van der Waals, void, thermal, and interaction volume. The total change in the PMV is positive. This is primarily due to the growth of void space within the peptide, which is canceled in part by the volume reduction resulting from the increase in the electrostatic interaction between the peptide and water molecules. The changes in the void and thermal volume of the coil structures are widely distributed and tend to compensate each other.