PrimeX - Protein structure prediction Software

PrimeX uses the OPLS-AA force field along with state-of-the-art technologies to refine protein crystal structures for computational drug discovery

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The prevailing geometric restraints employed in protein crystallography apply experimental bond length and angle terms as well as other restraint terms that have been subsequently added. However, some potential issues arise when refined structures are used in downstream computational modeling.

Two key characteristics of protein crystal structures that could affect the accuracy of subsequent structure-based modeling are:

• High-energy contacts interfere with computational chemistry calculations, and are often removed by the application of restrained energy minimization to the crystal structure; the danger with this procedure is the introduction of changes in the structure not supported by the X-ray data.
• Most protein crystal structures at typical resolutions do not include hydrogens in the model, which must be added after the end of refinement for many molecular mechanics calculations.

Traditionally, attempts to remediate the aforementioned issues are done after refinement, which shifts the control of structural results away from the scientists who are most familiar with the interpretation of diffraction experiments. PrimeX directly addresses these concerns by restraining protein geometry to OPLS-AA (one of the most accurate and widely-deployed force fields for studying protein/ligand systems) during X-ray refinement, and by adding hydrogens during refinement and fully accounting for their existence in all energy computations.

Furthermore, just as the inclusion of hydrogen atoms provides important information for structure validation of refinement results, PrimeX also features improved accounting of non-bonded interactions during refinement, which are central to understanding ligand binding. Thus, PrimeX provides a complete environment that facilitates refinement and produces accurate structures suitable for further computational modeling.

Software Link: PrimeX - Protein structure prediction Software

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Protein Preparation Wizard - Protein structure prediction Software

An easy-to-use tool for correcting common structural problems and creating reliable, all-atom protein models. Protein Preparation Wizard is a robust solution for ensuring a reasonable starting point at the outset of structure-based drug design projects, making it an attractive tool of choice for any chemist whose work relies upon accurate protein models.

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Successful structure-based modeling projects demand not only accurate software, but accurate starting structures as well. Left untreated, common problems with experimentally-derived structures can lead to wasted time and resources. Schrodinger's Protein Preparation Wizard is designed to help researchers ensure structural correctness at the outset of a project, equipping them with a high-confidence structure ideal for use with a wide variety of modeling applications.

Experienced modelers know that accurate starting structures are a prerequisite for successful computational drug design. Unfortunately, even when working with a high-resolution x-ray crystallographic structure, researchers can spend considerable time and effort correcting common problems such as missing hydrogen atoms, incomplete side chains and loops, ambiguous protonation states, and flipped residues.

The Protein Preparation Wizard aggregates, automates, and integrates the most frequently used tools and techniques in structure preparation, without shoehorning the researcher into a single inflexible process. Throughout the preparation workflow, a user can choose whether or not to apply any given operation, and because intermediate structures are all organized in the project table, it becomes trivial to share any result with a colleague or use outside applications when a specialized approach may be called for.

More than just a handful of utilities for minor structural corrections, the Protein Preparation Wizard is a robust solution for ensuring a reasonable starting point at the outset of structure-based drug design projects, making it an attractive tool of choice for any chemist whose work relies upon accurate protein models.

Software Link : Protein Preparation Wizard - Protein structure prediction Software

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QSite - Drug design software

QSite applies quantum mechanics to the reactive center of a protein active site and molecular mechanics to the rest of the system. Its accuracy allows detailed understanding of reactions involving proteins, making it a powerful tool for lead optimization.

Details
Insight into reactive chemistry is crucial to understanding the mechanism of drug receptor interactions in systems where the ligand is covalently bound to the receptor. For example, it's necessary to study the transition states between bound and unbound forms in order to design antibiotics that are not subject to inactivation by beta lactamases. Classical molecular mechanics (MM) methods cannot describe the electronic changes during a reaction, and are ill-equipped to address ligand-receptor interactions in systems containing metals.

Ab initio quantum mechanics (QM) is required to study reactive chemistry or interactions involving transition metals in a protein environment. However, even with today's computer technology, full QM calculations of entire proteins are still intractable.

Mixed QM/MM calculations provide the ideal solution by separating out the reactive core, which can be accurately described with QM, while treating the remainder of the complex more efficiently with MM. While QM/MM may not be needed for every structure-based drug design project, many important systems cannot be effectively addressed by any other computational means. QM/MM is therefore a key component in the arsenal of computational drug discovery.

Software Link : QSite - Drug design software

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RAPTOR - Protein Structure Prediction Software

RAPTOR is an innovative software tool designed for accurate protein structure prediction. It combines advanced analysis tools in one integrated software solution and provides three different threading methods.

Structure-based drug design approaches have been an integral part of the drug discovery process and have made a profound contribution at many pharmaceutical companies. As more and more structural information becomes available, a variety of practical structure-based techniques have been developed to accelerate the development at all stages of the drug discovery process. In spite of that, structure-based drug design requires a significant amount of structural resources from experimental methods. The recent explosion in genomic data has resulted in millions of protein sequences and researchers cannot afford to perform XRAY or NMR analysis on every protein. Currently, only 40 000 structures are stored in the PDB database. Consequently, pharmaceutical companies are increasingly turning to bioinformatics technologies which can reduce drug discovery and development costs. The practical role of protein structure prediction is now more important than ever.

Given a target protein sequence, if there is a homologous protein with known 3D structure, it can be found by using sequence search tools like PSI-BLAST or BLASTP. The target's structure is then built from the known structure. However, when the sequence homology is not significant, i.e. less than 25%, PSI-BLAST and BLASTP can not come up with a confident hit. Unlike PSI-BLAST or BLASTP, which simply does a sequence search, protein threading (fold recognition) makes use of both homology and structure information. It scans the protein sequence with an unknown structure against a database of known structures. By using a scoring function and conducting compatibility analysis between three-dimensional structures and linear protein sequences, the best structural template will be identified from which to build the sequence's structure. As a result, protein threading gives a superior prediction than homology modeling when there is marginal sequence homology. A comparison between RAPTOR and PSI-BLAST in CASP competitions can be found here.

RAPTOR is an innovative software tool designed for accurate protein structure prediction. It combines advanced analysis tools in one integrated software solution and provides three different threading methods. RAPTOR's unique integer programming optimization approach is most effective for finding structure templates of targets with low sequence homology and is able to generate high quality models. The easy-to-use interface and easy-to-understand E values are ideal for beginners and experts. Above all, the intuitive display of the output enables users to understand the results simply at a glance.

Software Link: RAPTOR -  Protein Structure Prediction Software

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