Computer Assisted Modeling Contributions of Computational Approaches to Elucidating Macromolecular Structure and Function (1987) / Chapter Skim
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7 Functional Aspects of Proteins and Nucleic Acids
7 Functional Aspects of Proteins and Nucleic Acids
Pages 106-130
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From page 106... ...
Empirical potentials in molecular dynan~cs or molecular mechanics calculations are approximations chosen to mode! thermodynamically stable minima in energy surfaces.
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From page 107... ...
In these cases the ah initio quantum mechanics calculation, which by its nature Is currently restricted to systems of a few atoms, will have to be performed on a fragment or fragments of the chemically reacting species. It is not yet clear how this can be done without introducing large errors.
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From page 108... ...
Because of the empirical character of the EVE method and a lack of general experience with it, these conclusions await confirmation through further study with the EVB method and ab initio methods. Given the great interest in the theory of enzyme catalysis, investigators have already begun to apply a combination of ab initio quantum mechanics and molecular dynamucs (Rao et al., 1987~.
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From page 109... ...
The problem here is that the amino acid sequence of the hypothetical protein, in general, specifies only two of the three bases in each codon of the gene. One way to resolve this issue is to choose a random third base (see Figure 7-2~.
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From page 111... ...
Even when the codon utilization statistics of the new expression vector are mimicked, complete protein folding does not necessarily occur. This suggests that third base redundancy may be partially used to control protein folding, especially for complex proteins.
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From page 112... ...
They began to diEuse to biochemical and genetics laboratories in academic and industrial institutions worldwide. Over the past 20 years, the manufacturers of computer and graphics hardware have begun to recognize that molecular graphics and modeling is a substantial market.
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From page 113... ...
have been identified, and collaborations are in place to insure that these machines, when they enter the commercial market, will be fully conditioned ~chemistry engines". The four functions, molecular energy computation, molecular configuration control, molecular graphics, and reasoning about molecular structure, will be integrated in one computer system.
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From page 114... ...
The central bottleneck to progress in protein design is our inability to predict protein tertiary structure from amino acid sequence. The notion put forth by Anfinsen 25 years ago was that the amino acid sequence alone determines tertiary structure.
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From page 115... ...
Although we have learned much about these topics, there are unanswered questions that we must be able to answer before we will be able to make accurate predictions. Experience in Ligated Design Tom E~eranental Protein Structures One illustration of our current state of achievement is given by work on hemoglobin.
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From page 116... ...
Perutz and coworkers experimentally demonstrated several of the potential binding sites that a molecule might recognize in hemoglobin. Specifically, they solved the crystal structure of eight ligand-hemogiobin complexes and showed that there are at least six different positions on the protein at which a ligand night form a tight complex.
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From page 118... ...
Each of the bound ligands changes the structure of the proteins so little that the change is barely detectable, yet some of the ligands increase the gelling concentration, some decrease it, and others do not change it at all. This work makes it clear that even after studying structure and function of hemoglobin for 25 years, an investigator may still be puzzled by the functional consequences of the minute structural changes that accompany ligand binding.
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From page 119... ...
In the first use of color computer graphics ~ the design of ligands to bind to a protein, workers at the University of California at San Francisco used interactive potential energy calculations and molecular graphics to dock thyroxine analogues into the binding site In the crystallographic structure of pre-albumin (Blaney et al., 1982~. They designed and synthesized several more strongly bound ligands.
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From page 120... ...
We have discussed structure/activity studies of the binding of effecter molecules to putative sites in a protein of known structure. A separate body of research has focused on a complementary problem: relating the structures of several effecter molecules to one another ~ order to determine information about binding sites, often termed active sites, in proteins of unknown structure.
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From page 121... ...
In particular, current applications of receptor-mapping methods usually compare the location of the projection of ligand atoms to possible binding sites,
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From page 122... ...
, it is important that the developers of this methodology are actively pursuing the challenge of evaluating the reliability of linear free-energy equations for cases in which the protein structure Is known. In the case of dihydrofolate reductase, several investigators have compared the conclusions from QSAR and molecular graphics modeling of the inhibitors (Blaney et al., 1984~.
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From page 123... ...
For example, through such Replays we can distinguish between surfaces near positively charged, negatively charged, hydrogen-bond accepting, hydrogen-bond donating, and hydrophobic regions of the protein. Another helpful tool used with the graphics display is the immediate read-out of energy values as the ligand is docked into a putative binding site and as bonds in the ligand and/or the protein are rotated to facilitate the docking.
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From page 124... ...
Conformational responses to ligand binding may form the basis of the selectivity of ligands for very similar proteins. Evidence from crystallography, QSAR, and molecular graphics suggests that conformational changer in the enzyme in response to the bin(ling of ligands is responsible for the selectivity of trirnethoprim for bacterial dihydrofolate reductases in contrast to vertebrate enzymes
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From page 125... ...
Since there is no experimentally established three-dimensional structure of a membrane-bound receptor, for this type of protein we depend on indirect observation and inference for our notions about conformation and conformational changes in response to ligand binding. Current concepts of receptor function usually invoke a conformational change as part of the transduction of the signal of a binding event into the ultimate biochemical and physiological response.
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From page 126... ...
The method of matching ligand shapes to protein cavities is helpful in predicting such alternate binding modes. However, it is currently limited because it considers only the correspondence of the shape of the ligand and the binding site and not their possible flexibility or electrostatic and hydrophobic contributions to binding energy.
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From page 127... ...
However, this is not necessarily true. For example, current evidence is that receptor kineses are present in the cell in high concentrations: the rate of phosphorylation of the receptor is apparently governed by the concentration of the cyclic nucleotide and the conformational state of the receptor and not the level of the enzyme.
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From page 128... ...
Other complications may also emerge when one is predicting function or designing ligands from predicted three-dimensional protein structures. First, the confidence in the exact coordinates of the protein structures will be lower.
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From page 129... ...
Consideration of protein structures based on DNA sequence may obscure the fact that the protein may function as part of a multisubunit assembly. Multiple subunit proteins are common.
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From page 130... ...
The current methods process a file of three-~nnensional coordinates of candidate molecules; this file is generated from experimental or theoretical studies and so is incomplete. Additionally, we cannot automatically compare a compound proposed by a computer program with those already in the world literature as tested for that activity, nor can we automatically detect if the proposed compound is iclentical or similar to compounds known to have some biological activity deleterious to that desired.
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