In silico prediction of mutant HIV-1 proteases cleaving a target sequence

HIV-1 protease represents an appealing system for directed enzyme re-design, since it has various different endogenous targets, a relatively simple structure and it is well studied. Recently Chaudhury and Gray (Structure (2009) 17: 1636 -- 1648) published a computational algorithm to discern the specificity determining residues of HIV-1 protease. In this paper we present two computational tools aimed at re-designing HIV-1 protease, derived from the algorithm of Chaudhuri and Gray. First, we present an energy-only based methodology to discriminate cleavable and non cleavable peptides for HIV-1 proteases, both wild type and mutant. Secondly, we show an algorithm we developed to predict mutant HIV-1 proteases capable of cleaving a new target substrate peptide, different from the natural targets of HIV-1 protease. The obtained in silico mutant enzymes were analyzed in terms of cleavability and specificity towards the target peptide using the energy-only methodology. We found two mutant proteases as best candidates for specificity and cleavability towards the target sequence

A Computational Methodology to Screen Activities of Enzyme Variants

We present a fast computational method to efficiently screen enzyme activity. In the presented method, the effect of mutations on the barrier height of an enzyme-catalysed reaction can be computed within 24 hours on roughly 10 processors. The methodology is based on the PM6 and MOZYME methods as implemented in MOPAC2009, and is tested on the first step of the amide hydrolysis reaction catalyzed by Candida Antarctica lipase B (CalB) enzyme. The barrier heights are estimated using adiabatic mapping and are shown to give barrier heights to within 3kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a small model system. Relatively strict convergence criteria (0.5kcal/(mol{\AA})), long NDDO cutoff distances within the MOZYME method (15{\AA}) and single point evaluations using conventional PM6 are needed for reliable results. The generation of mutant structure and subsequent setup of the semiempirical calculations are automated so that the effect on barrier heights can be estimated for hundreds of mutants in a matter of weeks using high performance computing

Magnetic anisotropy terms in [110] MBE grown REFe2 films involving the strain term ???

The magnetic anisotropy parameters in [110] MBE grown films of REFe2 compounds are not the same as those in the bulk. This is due to the presence of a shear strain εxy, frozen in during crystal growth. In this paper, calculated magnetic anisotropy parameters for [110] MBE grown REFe2 films, that directly involve the shear strain εxy, are presented and discussed. In addition to the usual first order Callen and Callen term K˜'2, there are nine second order terms six of which involve cross terms between εxy and the cubic crystal field terms B4 and B6. Two of the second order cross terms are identified as being important: K˜"242(T) and K˜"262(T). Of these, the rank-two term K˜"242(T) dominates over a large temperature range. It has the same angular dependence as the first order term K˜'2, but with a more rapid temperature dependence. The correction at T = 0K for TbFe2, DyFe2, HoFe2, ErFe2, and TmFe2, amounts to ~+9.2%, -13.9%, -11.6%, +22.7%, and 27.1%, respectively. Similar comments are made concerning the rank-four K˜"264(T) term

Non-universal gaugino masses from non-singlet F-terms in non-minimal unified models

In phenomenological studies of low-energy supersymmetry, running gaugino masses are often taken to be equal near the scale of apparent gauge coupling unification. However, many known mechanisms can avoid this universality, even in models with unified gauge interactions. One example is an F-term vacuum expectation value that is a singlet under the Standard Model gauge group but transforms non-trivially in the symmetric product of two adjoint representations of a group that contains the Standard Model gauge group. Here, I compute the ratios of gaugino masses that follow from F-terms in non-singlet representations of SO(10) and E_6 and their sub-groups, extending well-known results for SU(5). The SO(10) results correct some long-standing errors in the literature.Comment: 13 page