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Biomedical subjects

A Warshel

Publications and source records attributed to A Warshel.

At least 73 records · Page 4Linked to original sources
PubMed1984

Macroscopic models for studies of electrostatic interactions in proteins: limitations and applicability.

The validity of macroscopic models for calculations of electrostatic energies in proteins is examined. The Tanford-Kirkwood (TK) model is extended to include the self energy of the ionized groups. It is shown that ionized groups cannot exist inside nonpolar regions of proteins and argued that the experimental finding of ions inside proteins proves that the corresponding local environment is polar. The modified TK model (MTK model), which adjusts charge-charge interactions by the corresponding solvent accessibilities, is found to be inconsistent with the TK model, on which it is based. The MTK model corresponds to a polar interior whereas the TK model assumes a nonpolar interior. It is shown that models that assume a high dielectric constant for proteins give reasonable results for interactions between charged groups at equilibrium. It is then explained why, in contradiction to common belief, protein interiors are polar around charged groups. It is argued that in focusing on charge-charge interactions one overlooks the key contribution of the protein dipoles in determining the self energy of charges in the interior of proteins.

Hydrogen-Ion Concentration↗
PubMed1984

Dynamics of enzymatic reactions.

The detailed molecular dynamics of an actual bond-breaking event in a fluctuating enzyme substrate complex is simulated. The method developed allows one to explore what type of fluctuations are involved in enzymatic reactions and to evaluate entropic contributions to enzyme catalysis. The fluctuations of the enzyme electrostatic potential are found to be a key dynamical factor in reactions that involve a large change in the polarity of the reacting bonds.

Catalysis↗
PubMed1983

Converting structural changes upon oxidation of cytochrome c to electrostatic reorganization energy.

The observed X-ray structural differences between reduced and oxidized cytochrome c are converted to electrostatic energy. This conversion is used to estimate the protein reorganization energy which determines the protein contribution to the activation barrier for the electron transfer reaction. It is shown that the reorganization energy of cytochrome c is much smaller than the corresponding energy for electron transfer in water and that this is consistent with the role for cytochromes as electron transfer catalysts.

Cytochrome c Group↗
PubMed1981

Calculations of enzymatic reactions: calculations of pKa, proton transfer reactions, and general acid catalysis reactions in enzymes.

A method that allows one to correlate available X-ray data with activation free energies of enzymatic reactions is presented. This method is based on the empirical valence bond approach which uses experimental information to evaluate the energies of the valence bond resonance forms involved in a reaction and then calculates the environment-dependent stabilizations of the ionic resonance forms in the enzyme and in solution and correlates them with the rate acceleration by the enzyme. The method is reliable since it is based on calibration of potential surfaces by solution experiments and on transfer of the calibrated surface to the enzyme active site, using only simple calculations of electrostatic interactions. The close relation between the method and the intuitive valence bond description of bond-breaking bond-making reactions provides a new insight into enzymatic reactions, describing them as crossing between covalent and ionic valence bond resonance forms. Such a description correlates the stabilization of the ionic resonance forms by the enzyme active site with the enzyme catalytic activity. The paper considers the energetics of several enzymatic processes, including ionization, of acidic groups in enzyme active sites, stability of ion pairs in enzymes and in solutions, proton transfer reactions, and general acid catalysis reactions. The calculations support the idea that enzymes can be viewed as "supersolvents" that stabilize (solvate) ionic transition states more effectively than do aqueous solutions.

Enzymes↗
PubMed1981

Electrostatic control of the efficiency of light-induced electron transfer across membranes.

The energetics and efficiency of light-induced electron transfer across membranes is examined on a molecular level. It is found that the activation energies that control the efficiency are determined by the solvation energies of the charge-transfer states, the redox potentials of the donors and acceptors, and the dielectric relaxation of the system. The formalism developed allows one to assess the efficiency of any artificial photosynthetic system in terms of its molecular components and their local environment. It is pointed out that the key problem in designing an efficient photosynthetic system is the transfer of a charge through a low dielectric environment and that this problem cannot be overcome by choosing the position of the primary donor and acceptor in the membrane. It is predicted that artificial photosynthetic systems can be optimized by placing the acceptors in polar sites that provide a large effective dielectric constant and low dielectric relaxation and by arranging the acceptors in order of increasing redox potentials. The implication regarding bacterial photosynthesis is discussed.

Journal Article↗
PubMed1981

Empirical valence bond calculations of enzyme catalysis.

A method that allows one to correlate available x-ray data with activation free energies of enzymic reactions was presented. The method is an Empirical Valence Bond (EVB) approach that uses experimental information to evaluate the energies of the valence bond resonance forms and then calculates the environment-dependent stabilizations of the ionic resonance forms in the enzyme and in solution in order to correlate them with the rate enhancement by the enzyme. The reliability of the method is based on calibration of potential surfaces using solution experiments and on transfer of the calibrated surface to the enzyme active site using only simple electrostatic calculations. The close relation between the method and the intuitive description of bonding provides a new insight into enzymic reactions, describing them as surface crossings between covalent and ionic resonance forms. Such a description clarifies how the stabilization of the ionic resonance forms by the enzyme determines its catalytic activity.

Catalysis↗
PubMed1980

Role of the chlorophyll dimer in bacterial photosynthesis.

The role of a special dimer (D) of bacteriochlorophyll molecules in bacterial photosynthesis was examined by calculations of the rates of electron transfer reactions in a system of the dimer and a bacteriopheophytin (BPh) molecule. It was found that the dependence of the potential surfaces of D on the distance between the monomers allows a fast light-induced electron transfer from D to BPh but only a slow back reaction (reduction of D(+) by BPh(-)). The same potential surfaces allow efficient reduction of D(+) by cytochrome c. Possible advantages of greatly different values of the electronic matrix elements for the forward and back reactions are pointed out. It is suggested that the electrostatic interaction between D(+) and an ionized group of the protein might play an important role in the photosynthetic reaction.

Journal Article↗
PubMed1978

Energetics of enzyme catalysis.

Quantitative studies of the energetics of enzymatic reactions and the corresponding reactions in aqueous solutions indicate that charge stabilization is the most important energy contribution in enzyme catalysis. Low electrostatic stabilization in aqueous solutions is shown to be consistent with surprisingly large electrostatic stabilization effects in active sites of enzymes. This is established quantitatively by comparing the relative stabilization of the transition states of the reaction of lysozyme and the corresponding reaction is aqueous solution.

Binding Sites↗
PubMed1978

Charge stabilization mechanism in the visual and purple membrane pigments.

The effects of charged groups of rhodopsin and bacteriorhodopsin on the potential energy surface of their chromophore are examined, taking into account the protein dielectric effect. It is found that the barriers for twisting double bonds of an isolated chromophore can be drastically reduced when the chromophore interacts with the protein charges. New types of local minima are found in the ground-state potential surface of the protein-chromophore complex. These minima correspond to "charge-stabilized intermediates" which are formed when a shift of the chromophore positive charge to the ring is stabilized by the ionization of a properly placed acidic group of the protein and by partial alternation of the bond lengths of the chromophore. It is suggested that the absorption of light by rhodopsin and bacteriorhodopsin may be used not only for isomerization about double bonds, but also for trapping such charge-stabilized intermediates. Thus, for example, it is concluded that prelumirhodopsin might be still in the cis configuration. Both the mechanism of the proton pump system of the purple membrane and the dark reaction of the visual and purple membrane pigments are considered. The connection between the finding of the present work and the mechanism of storage of light energy in photobiology is indicated.

Bacteriorhodopsins↗
PubMed1977

Energy-structure correlation in metalloporphyrins and the control of oxygen binding by hemoglobin.

The contribution of the porphyrin skeleton to the potential energy surface metalloporphyrins is calculated by the semiempirical method of quantum mechanical extension of the consistent force field to eta electron molecules. This calculation makes it possible to correlate the observed structure of metalloporphyrins with the strain energy of the porphyrin skeleton. It is found that the out-of-plane metal displacement in pentacoordinate heme systems is due to both the restricted size of the porphyrin hole and the "1-3" steric interaction between the axial ligand and the heme nitrogens. The main components of the active site of hemoglobin are simulated by a histidine-heme-oxygen system. The energy surface of this system provides a quantitative explanation for the control of ligand binding by hemoglobin. It is shown that the heme acts as a diaphragm, designed to provide simultaneous binding to the histidine and the sixth ligand under the steric requirements of the 1-3 interactions. The dependence of the hemoglobin potential surface on the distance between the proximal histidine and the heme plane is evaluated for the R and T states, using the calculated heme potential and the observed energy of heme-heme interaction.

Binding Sites↗
PubMed1976

Bicycle-pedal model for the first step in the vision process.

Computer simulation of the molecular dynamics of retinal during its photoisomerisation inside a restrictive active site gives a detailed model for the sequence of events in the first step of the vision process. It is proposed that the prelumirhodopsin intermediate contains a strained all-trans retinal molecule produced directly and rapidly from the 11-cis, 12-s-trans conformation in rhodopsin by a bicycle-pedal isomerisation. The model reproduces the main experimental observations and explains how the protein makes the photoisomerisation path unique.

Binding Sites↗
PubMed1975

Computer simulation of protein folding.

A new and very simple representation of protein conformations has been used together with energy minimisation and thermalisation to simulate protein folding. Under certain conditions, the method succeeds in "renaturing" bovine pancreatic trypsin inhibitor from an open-chain conformation into a folded conformation close to that of the native molecule.

Amino Acid Sequence↗