Abstract
A collection of computer tools designed for amino acid sequence
analysis, model building and molecular simulation of proteins is reviewed,
with emphasis on case studies of three proteins for which X ray structures
were not available but sequence and mutant data warranted an investigation by
computer aided molecular modelling.A program, MaxSprout, was written for
building a full set of protein coordinates given only a Ca trace, The
algorithm optimized backbone stereochemistry by combining fragments taken from
a database of known structures, taking care that they overlap smoothly.
Sidechains were added from a rotamer library, and optimized for sterical fit.
The results obtained with this simple algorithm compare favourably with (a)
manual and (b) time consuming computerized search methods.Structural models of
the redox centres in cvtochrome oxidase were based on a synthesis of
evolutionary conservation, predicted membrane topography and known
spectroscopic properties.The redox centres in subunit I were modelled with
four helical segments treated as rigid blocks of hard spheres.Subunit 1I was
proposed to contain a copper binding domain homologous to that of the blue
copper proteins.The structural models are in agreement with many experimental
observations.A structural model of Bacillus stearothermophilus a amylase was
built based on a multiple sequence alignment of a amylases.There was 24 %
sequence identity to Taka amylase A, which was used as a 3 D template.The
changes in the activity of ninety eight mutant enzymes could be rationalized
on the basis of their location in the 3 D model.The coherence of model and
mutant data support the structural ideas.Oxazolone binding affinities of a
series of natural anti oxazolone antibodies with known sequences but unknown
structures were used to test the performance of theoretical methods for future
protein design purposes.A strongly homologous template was available to model
the protein, and the ligand was docked using a combination of interactive
graphics and molecular dynamics.The comparison of modelled complexes between
the ligand and idiotypic or mature antibody suggest plausible explanations for
the experimentally observed increase in affinity.
Original language | English |
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Qualification | Doctor Degree |
Awarding Institution |
|
Award date | 28 May 1990 |
Place of Publication | Espoo |
Publisher | |
Print ISBNs | 951-38-3576-6 |
Publication status | Published - 1990 |
MoE publication type | G5 Doctoral dissertation (article) |
Keywords
- CAD
- molecular structure
- amino acids
- computer programs
- enzymes
- stereochemistry